CN103402977B - Ingenol-3-acylate III and ingenol-3-carbamate - Google Patents

Ingenol-3-acylate III and ingenol-3-carbamate Download PDF

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CN103402977B
CN103402977B CN201180068162.3A CN201180068162A CN103402977B CN 103402977 B CN103402977 B CN 103402977B CN 201180068162 A CN201180068162 A CN 201180068162A CN 103402977 B CN103402977 B CN 103402977B
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ingenol
manthanoate
compound
methyl
alkyl
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CN103402977A (en
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G·格鲁-索伦森
梁锡福
T·赫贝尔
K·曼森
P·韦德索
T·维菲安
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Leo Laboratories Ltd
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Leo Laboratories Ltd
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Abstract

The present invention relates to separately or apply in the treatment with one or more other medicines active compound, the compound of Formula I, its pharmacologically acceptable salt, hydrate or the solvate that have disease or the situation responded or have a response to necrosis induced for the stimulation that stimulation has response, Human Keratinocytes IL-8 discharges preventing, treat or improve centering granulocyte oxidative burst, wherein R is optionally by heteroaryl that R7 replaces; Or R is Heterocyclylalkyl or heterocycloalkenyl, it is optionally replaced by R8; Or R is X, wherein X Shi – NR11R12.

Description

Ingenol-3-acylate III and ingenol-3-carbamate
Invention field
The present invention relates to the derivative of new 3-O-acyl group-ingenol and 3-O-formamyl-ingenol and derivative and they thereof and be used as medicine and purposes in the treatment.Present invention also offers the pharmaceutical composition that comprises described compound and the method by described compounds for treating disease.
Background of invention
PEP005 (PEP005, ingenol methyl butene acid esters) is separated the Diterpene Ester from various Euphorbia species, particularly the ingenol family of the root of Beijing euphorbia, southern Europe (Euphorbiapeplus).This compound carries out clinical development at present, is used for the treatment of actinic keratosis and nonmelanoma skin cancer.
WO99/08994 describes from the application cancer and other tumor disease and actinic keratosis or solar keratosis of euphorbia separating compound and these compounds.
From various Euphorbia species, isolate ingenol-3-acylate, mainly saturated and unsaturated aliphatic lipid acid [H.Gotta, Z.Naturforschung, (1984), 39b, the 683-94 of long-chain; K.Abo, Fitoterapia, (1988), 244-46, S.Zayed, J.CancerRes.Clin.Oncol. (2001), 127,40-47].In addition, a few ingenol-3-acylate (B.Sorg etc., Z.Naturforsch., (1982), 37b, 748-56) has been prepared by semi-synthetic.To some of description in these ingenol derivatives, and be strong impulse agent and strong tumor promoter [B.Sorg etc., Z.Naturforsch., (1982), 37b, 748-56 after tested; B.Sorg etc., Carcinogenesis, (1987), 8,1-4].
Except aliphatic ingenol fat, the aromatics fat of ingenol is also known.Describe milliamine (Milliamine) C (ingenol-3-anthranilate derivatives) (Marston, A.PlantaMedica, (1983), 47,141-47).Also describe ingenol-3-benzoic ether (Sorg, B.; ZNaturforschung, (1982), 37b, 748-56).
Heteroaromatic or heterocycle 3-O-acyl group ingenol derivative are not yet open in the past.
Ingenol-3-carbamate is not yet open in the past.The different ingenol carbamate replaced is refer in US5955501, US5891906, US5891870 and WO9202484.
Angelicic acid and angelate (being present in PEP005) are easy to occur the isomerization of double bond and form tiglate, particularly [Beeby, P. at basic ph, TetrahedronLett. (1977), 38,3379-3382, Hoskins, W.M., J.Chem.Soc.PerkinTrans.1, (1977), 538-544, Bohlmann, F. etc., Chem.Ber. (1970), 103,561-563].
In addition, known ingenol-3-acylate is unstable, because they can reset generation ingenol-5-acylate and ingenol-20-acylate [Sorg; B. etc., Z.Naturforsch., (1982); 37B, 748-756].
PEP005 is considered to have dual function pattern: 1) carry out inducing cell death by direct cytotoxicity or cell death inducing; with 2) raise and activate with neutrophil leucocyte the immunostimulation (Rosen taken as the leading factor; R.H.; Deng; JAmAcadDerm (2011), electronic publishing Nov2011; Ersvaer, E., etc., Toxins, (2010), 2,174-194).The promoting agent of nanomolar concentration cause the classics of protein kinase C (PKC) with the activation of new isoform and adjustment, particularly importantly PKC δ.By PKC activation δ, this promoting agent induction permissive cell apoptosis (Hampson, P., etc., Blood, (2005), 106,1362-1368; Cozzi, S.J., etc., CancerRes, (2006), 66,10083-10091).Under high micro-molar concentration, observe rapid cellular toxic action to cancer cells (Ogbourne, S.M., etc., CancerRes (2004), 64,2833-2839).By activating various PKC isoform, this promoting agent is inducible proinflammatory effect also, comprises the release (Challacombe of pro-inflammatory mediator; J.M., etc., JImmunol (2006); 177; 8123-8132), the activation of blood vessel endothelium (Hampson, P., etc.; CancerImmunolImmunother; (2008), 57,1241-1251); By induction keratinocyte in interleukin 8 produce neutrophil leucocyte chemotaxis and by adjuvanting properties produce in animal model CD8+ cell specific anti-cancer immunne response (Le, T.T., etc., Vacccine, (2009), 27,3053-3062).
Carry out inducing cell death by direct cytotoxicity or cell death inducing to can be used for treating the situation relevant with hyperplasia or tumour with the compound of the immunostimulation raised with activate and the pattern that plays a dual role by relating to neutrophil leucocyte.Unwanted cells can be reduced by the compound of primary and/or secondary necrosis inducing cell death and the compound that shows apoptosis-promoting effect grow and remove unwanted cells; in addition, the stimulation of innate immune response and adjuvant effect can increase the biologically to exception or transformant.
Can be used for treating cosmetic conditions, because these compounds can kill or remove unwanted tissue or cell by the compound of primary and/or secondary necrosis inducing cell death.
Need the new ingenol derivative found by cytotoxicity or apoptosis induction necrocytosis and/or induction of immunity hormesis.
The invention provides heterocycle 3-O-acyl group ingenol derivative and 3-O-formamyl ingenol derivative; it can be used for treating the situation relevant with the use of PEP005, or is used for the treatment of the situation being subject to by cytotoxicity or the cell death inducing impact of inducing cell death and/or affecting by immunostimulation.
The compounds of this invention can stimulate the oxidative burst of neutrophil leucocyte, and it is a part for innate immune response.
The compounds of this invention can stimulate the release of keratinocyte IL-8, thus induction of immunity hormesis.
Some the compounds of this invention can induce quick necrosis.
Some the compounds of this invention shows activity in B16 murine melanoma model, and this represents that this compound has anti-tumor activity and can kill the cell of tumour and conversion.
Some the compounds of this invention shows satisfactory stability.
Summary of the invention
In one embodiment, the invention provides compound of Formula I and pharmacologically acceptable salt, prodrug, hydrate and solvate:
Wherein R is heteroaryl, its optionally replace by one or more substituting group independently selected from R7;
Or R is Heterocyclylalkyl or heterocycloalkenyl, wherein said Heterocyclylalkyl or heterocycloalkenyl optionally replace by one or more substituting group independently selected from R8;
Or R is X;
R7 represents halogen, cyano group or hydroxyl;
Or R7 represents (C 1-C 4) alkyl, (C 2-C 4)-alkenyl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, arylalkyl, hetercycloalkylalkyl or (C 3-C 7)-cycloalkylalkyl, wherein said (C 1-C 4) alkyl, (C 2-C 4)-alkenyl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, arylalkyl, hetercycloalkylalkyl or (C 3-C 7)-cycloalkylalkyl optionally replace by one or more substituting group independently selected from R9;
Or R7 represents-NRaCORb ,-CONRaRb ,-COORc ,-OCORa ,-ORa ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-SRa or-NRaRb;
R9 represents halogen, cyano group, hydroxyl, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl ,-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa or=O;
R8 represents halogen, cyano group or hydroxyl;
Or R8 represents (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, heteroaryl, (C 3-C 7)-cycloalkyl or Heterocyclylalkyl, wherein said (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, heteroaryl, (C 3-C 7)-cycloalkyl or Heterocyclylalkyl optionally replace by one or more substituting group independently selected from R10,
Or R8 represents-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa ,=O ,=N-ORa ,-O-N=CRaRb, NRaRb or-C (O) N (Ra) O-Rb;
R10 represents halogen, cyano group, hydroxyl, (C 1-C 4)-alkyl, (C 1-C 4) alkoxyl group, halo (C 1-C 4) alkyl, halo (C 1-C 4) alkoxyl group, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl ,-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa or=O;
Ra and Rb represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
Rc represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C x) alkyl, cyano group (C 1-C x) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
X Dai Biao – NR11R12;
Wherein R11 and R12 represents hydrogen independently,
Or
Wherein R11 and R12 represents (C independently 1-C 6) alkyl, (C 2-C 6) alkenyl or (C 2-C 6) alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenyl alkyl, arylalkyl, heteroarylalkyl, hetercycloalkylalkyl, heterocycloalkenyl alkyl, alkyl-cycloalkyl, alkylcycloalkenyl, alkylaryl, miscellaneous alkyl aryl or Alkyl cycloheteroalkyl, wherein said (C 1-C 6) alkyl, (C 2-C 6) alkenyl or (C 2-C 6) alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenyl alkyl, arylalkyl, heteroarylalkyl, hetercycloalkylalkyl, heterocycloalkenyl alkyl, alkyl-cycloalkyl, alkylcycloalkenyl, alkylaryl, miscellaneous alkyl aryl or Alkyl cycloheteroalkyl optionally replace by one or more substituting group independently selected from R13;
R13 represents halogen, cyano group or hydroxyl,
Or R13 represents (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, (C 3-C 7) cycloalkyl, heteroaryl or Heterocyclylalkyl, wherein said (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, (C 3-C 7) cycloalkyl, heteroaryl or Heterocyclylalkyl optionally replace by the substituting group of one or more R14 of being selected from
Or R13 represents-NRdCORe ,-COORf ,-OCORd ,-CONRdRe ,-OCONRdRe ,-NRdCOORe ,-NRdCONRdRe ,-NRdSO 2re ,-NRdSO 2nRdRe ,-SO 2nRdRe ,-SO 2rd ,-S (O) Rd ,-ORd ,-SRd ,=O ,=N-ORd ,-O-N=CRdRe ,-NRdRe or-C (O) N (Rd)-ORe,
Wherein Rd and Re represents hydrogen, (C independently 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
Rf represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl; R14 represents halogen, hydroxyl, cyano group, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, halo (C 1-C 4) alkyl, halo (C 1-C 4) alkoxyl group, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl ,-NRdCORe ,-COORf ,-OCORd ,-CONRdRe ,-OCONRdRe ,-NRdCOORe ,-NRdCONRdRe ,-NRdSO 2re ,-NRdSO 2nRdRe ,-SO 2nRdRe ,-SO 2rd ,-S (O) Rd ,-ORd ,-SRd or=O.
In one embodiment, the invention provides the formula I as medicine.
In one embodiment, the invention provides the purposes of formula I in preparation of pharmaceutical compounds.
In one embodiment, the invention provides pharmaceutical composition, hydrolyzable ester and pharmaceutically acceptable carrier or vehicle in its contained I or its pharmaceutically useful steric isomer, salt or body.
In one embodiment, the invention provides the pharmaceutical composition being suitable for topical, hydrolyzable ester and pharmaceutically acceptable carrier or vehicle in its contained I or its pharmaceutically useful steric isomer, salt or body.
In one embodiment, the invention provides the formula I being used for the treatment of, preventing, improving or preventing the physiological conditions relevant with hyperplasia or tumour or disease.
In one embodiment, the invention provides formula I for the preparation for the treatment of, improve or prevention the physiological conditions relevant with hyperplasia or tumour or disease medicine in purposes.
In one embodiment, the invention provides prevention, treatment, improve or the prevention physiological conditions relevant with hyperplasia or tumour or the method for disease, the method comprises the individuality for the treatment of to needs and uses above formula I.
In one embodiment, the invention provides the formula I being used for the treatment of or improving beauty treatment indication.
In one embodiment, the invention provides the purposes of formula I in the medicine for the preparation for the treatment of or improvement beauty treatment indication.
In one embodiment, the invention provides the method for the treatment of or improvement beauty treatment indication, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides pharmaceutical composition, it comprises hydrolyzable ester in the formula I combined with one or more other therapeutic activity agent or its pharmaceutically useful steric isomer, salt or body.
Detailed Description Of The Invention
One embodiment of the invention provide compound of Formula I and pharmacologically acceptable salt, prodrug, hydrate and solvate:
Wherein R is heteroaryl, its optionally replace by one or more substituting group independently selected from R7;
Or R is Heterocyclylalkyl or heterocycloalkenyl, each in them is all optionally replaced by one or more substituting group independently selected from R8;
Or R is X;
R7 represents halogen, cyano group or hydroxyl;
Or R7 represents (C 1-C 4) alkyl, (C 2-C 4) alkenyl, (C 3-C 7) cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, each in them is all optionally replaced by one or more substituting group independently selected from R9;
Or R7 represents-NRaCORb ,-CONRaRb ,-COORc ,-OCORa ,-ORa ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-Sra or-NRaRb;
R9 represents halogen, cyano group, hydroxyl, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl ,-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa or=O;
R8 represents halogen, cyano group, hydroxyl;
Or R8 represents (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, heteroaryl, (C 3-C 7) cycloalkyl or Heterocyclylalkyl, each in them is all optionally replaced by one or more substituting group independently selected from R10,
Or R8 represents-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa ,=O ,=N-ORa ,-O-N=CRaRb, NRaRb or-C (O) N (Ra) O-Rb;
R10 represents halogen, cyano group, hydroxyl, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, halo (C 1-C 4) alkyl, halo (C 1-C 4) alkoxyl group, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl ,-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa or=O;
Ra and Rb represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
Rc represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C x) alkyl, cyano group (C 1-C x) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
X Dai Biao – NR11R12;
Wherein R11 and R12 represents hydrogen independently,
Or
Wherein R11 and R12 represents (C independently 1-C 6) alkyl, (C 2-C 6) alkenyl or (C 2-C 6) alkynyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenyl alkyl, arylalkyl, heteroarylalkyl, hetercycloalkylalkyl, heterocycloalkenyl alkyl, alkyl-cycloalkyl, alkylcycloalkenyl, alkylaryl, miscellaneous alkyl aryl or Alkyl cycloheteroalkyl, they are optionally replaced by one or more substituting group independently selected from R13;
R13 represent halogen, cyano group, hydroxyl,
Or R13 represents (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, (C 3-C 7) cycloalkyl, heteroaryl or Heterocyclylalkyl, each in them is all optionally replaced by the substituting group of one or more R14 of being selected from,
Or R13 represents-NRdCORe ,-COORf ,-OCORd ,-CONRdRe ,-OCONRdRe ,-NRdCOORe ,-NRdCONRdRe ,-NRdSO 2re ,-NRdSO 2nRdRe ,-SO 2nRdRe ,-SO 2rd ,-S (O) Rd ,-ORd ,-SRd ,=O ,=N-ORd ,-O-N=CRdRe ,-NRdRe or-C (O) N (Rd)-ORe;
Wherein Rd and Re represents hydrogen, (C independently 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl;
Rf represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl; R14 represents halogen, hydroxyl, cyano group, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, halo (C 1-C 4) alkyl, halo (C 1-C 4) alkoxyl group, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl ,-NRdCOR e,-COORf ,-OCORd ,-CONRdRe ,-OCONRdRe ,-NRdCOORe ,-NRdCONRdRe ,-NRdSO 2re ,-NRdSO 2nRdRe ,-SO 2nRdRe ,-SO 2rd ,-S (O) Rd ,-ORd ,-SRd or=O.
Another embodiment of the invention provides above compound of Formula I and pharmacologically acceptable salt, prodrug, hydrate and solvate,
Wherein R is heteroaryl, its optionally replace by one or more substituting group independently selected from R7,
Or R is Heterocyclylalkyl or heterocycloalkenyl, each in them is all optionally replaced by one or more substituting group independently selected from R8,
R7 represents halogen, cyano group, hydroxyl;
Or R7 represents (C 1-C 4) alkyl, (C 2-C 4)-alkenyl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, they are all optionally replaced by one or more substituting group independently selected from R9; Or R7 represents-NRaCORb ,-CONRaRb ,-COORc ,-OCORa ,-ORa ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-SRa;
R9 represents halogen, cyano group, hydroxyl, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl ,-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa ,=O;
R8 represents halogen, cyano group, hydroxyl;
Or R8 represents (C 1-C 4)-alkyl, (C 2-C 4) alkenyl, aryl, heteroaryl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, each in them is all optionally replaced by one or more substituting group independently selected from R10,
Or R8 represents-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa ,=O;
R10 represents halogen, cyano group, hydroxyl, (C 1-C 4)-alkyl, halo (C 1-C 4) alkyl ,-NRaCORb ,-COORc ,-OCORa ,-CONRaRb ,-OCONRaRb ,-NRaCOORb ,-NRaCONRaRb ,-NRaSO 2nRaRb ,-NRaSO 2rb ,-SO 2nRaRb ,-SO 2ra ,-S (O) Ra ,-ORa ,-SRa ,=O;
Ra and Rb represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl;
Rc represents (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl.
One embodiment of the invention provide formula I, and wherein heteroaryl is different azoles base, pyridyl, quinolyl, isoquinolyl, indyl, furyl, thiazolyl, imidazolyl, pyrazolyl, azoles base, thienyl, pyrimidyl, 1,2,3-triazoles base, indazolyl, cinnolines base or 1,2-benzo azoles base.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base, pyridyl, quinolyl, isoquinolyl, indyl, furyl, thiazolyl, imidazolyl, pyrazolyl, azoles base, thienyl, pyrimidyl, 1,2,3-triazoles base, indazolyl, cinnolines base, 1,2-benzo azoles base, Imidazothiazole base, imidazopyridyl, pyrryl, isothiazolyl, tetrahydrochysene indazole base or di azoly.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base, furyl, pyrazolyl, thienyl or pyrryl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is furyl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base, furyl, pyrazolyl, thienyl or pyrryl, and wherein R7 represents (C 1-C 4) alkyl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base, furyl, pyrazolyl, thienyl or pyrryl, and wherein R7 represents (C 1-C 2) alkyl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl, and wherein heteroaryl is different azoles base or furyl and wherein R7 represent (C 1-C 2) alkyl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base, furyl, pyrazolyl, thienyl or pyrryl, and wherein R7 represents phenyl.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is different azoles base, furyl, pyrazolyl, thienyl or pyrryl, and wherein R7 represents phenyl or (C 1-C 4) alkyl and wherein R9 represent (C 1-C 4) alkyl, halogen or-ORa.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is indyl, indazolyl or tetrahydrochysene indazole base.
One embodiment of the invention provide formula I, and wherein R is heteroaryl and wherein said heteroaryl is indyl, indazolyl or tetrahydrochysene indazole base, and wherein R7 represents (C 1-C 4) Wan Ji Huo – OR a.
One embodiment of the invention provide formula I, and wherein R7 is independently selected from (C 1-C 4) alkyl, aryl or halogen one or many.
One embodiment of the invention provide formula I, and wherein R7 is independently selected from (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, arylalkyl, hetercycloalkylalkyl, (C 3-C 7)-cycloalkylalkyl, (C 3-C 7)-cycloalkyl, – COORc ,-ORa or halogen one or many.
One embodiment of the invention provide formula I, and wherein R7 is selected from phenyl, methyl, ethyl, sec.-propyl, Cl or Br.
One embodiment of the invention provide formula I, and wherein R7 is selected from phenyl, methyl, ethyl, sec.-propyl, the tertiary butyl, piperidyl, t-butyloxycarbonyl, benzyl, tetrahydropyrans ylmethyl ,-OCH 3, cyclopropyl, allyl group, Cvclopropvlmethvl, Cl, Br or I.
One embodiment of the invention provide above formula I, and wherein R9 is halogen or-ORa.
One embodiment of the invention provide above formula I, and wherein R9 is halogen ,-ORa, (C 1-C 4) alkyl or-SO 2ra.
One embodiment of the invention provide formula I, and wherein R9 is Cl, F or-OCH 3.
One embodiment of the invention provide above formula I, and wherein R9 is Cl, F ,-OCH 3, methyl or methyl sulphonyl.
One embodiment of the invention provide formula I, and wherein R is Heterocyclylalkyl.
One embodiment of the invention provide above formula I, and wherein R is Heterocyclylalkyl or heterocycloalkenyl.
One embodiment of the invention provide formula I, and wherein Heterocyclylalkyl is pyrrolidyl, piperidyl, morpholinyl or 5-oxabicyclo [2.2.2] octane.
One embodiment of the invention provide formula I, and wherein R8 is (C 1-C 4) alkyl.
One embodiment of the invention provide above formula I, and wherein R is Heterocyclylalkyl or heterocycloalkenyl and wherein said Heterocyclylalkyl or heterocycloalkenyl are pyrrolidyl, piperidyl, morpholinyl, 5-oxabicyclo [2.2.2] octyl, oxaspiro [4.5]-1-in last of the ten Heavenly stems thiazolinyl, oxo-thiazol base, dihydro-thiazolyl, oxo-pyranyl, azepan base, azabicyclic [3.2.2] nonyl, benzimidazole dihydrochloride base, quinoxalinyl, dihydro-iso indolyl, dihydroquinoline base, indolinyl or dihydro-quinoxaline base.
One embodiment of the invention provide above formula I, and wherein R is Heterocyclylalkyl and wherein said Heterocyclylalkyl is indolinyl, benzimidazole dihydrochloride base or dihydroquinoline base.
One embodiment of the invention provide formula I, and wherein R8 is methyl.
One embodiment of the invention provide formula I, and wherein R8 is (C 1-C 4) alkyl, aryl or=O.
One embodiment of the invention provide formula I, wherein R Shi – NR11R12.
One embodiment of the invention provide formula I, and wherein R11 and R12 represents hydrogen, (C independently 1-C 6) alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl or cycloalkylalkyl.
One embodiment of the invention provide above formula I, and wherein R11 and R12 represents hydrogen, (C independently 1-C 6) alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, Heterocyclylalkyl, hetercycloalkylalkyl, (C 2-C 6) alkenyl or (C 2-C 6) alkynyl.
One embodiment of the invention provide above formula I, and wherein R11 and R12 represents hydrogen, (C independently 1-C 6) alkyl, aryl or arylalkyl.
One embodiment of the invention provide above formula I, and wherein R11 and R12 represents hydrogen, (C independently 1-C 4) alkyl, cycloalkyl, phenyl or benzyl.
One embodiment of the invention provide above formula I, and wherein R11 and R12 represents hydrogen, (C independently 1-C 4) alkyl, phenyl or benzyl, wherein said (C 1-C 4) alkyl, phenyl or benzyl optionally replace by the substituting group of one or more R13 of being selected from, wherein R13 represents halogen, (C 1-C 4) alkyl or-ORa.
One embodiment of the invention provide formula I, and wherein R11 and R12 represents hydrogen, methyl, ethyl, sec.-propyl, phenyl, benzyl, cyclohexyl, indanyl, tetrahydro naphthyl, phenylethyl, Cvclopropvlmethvl or pyrazolyl independently.
One embodiment of the invention provide above formula I, and wherein R11 and R12 represents hydrogen, methyl, ethyl, sec.-propyl, phenyl, benzyl, cyclohexyl, indanyl, tetrahydro naphthyl, phenylethyl, Cvclopropvlmethvl, pyrazolyl, different independently azoles ylmethyl, cyclopentyl, cyclopropyl, pyridyl, piperidyl, tetrahydropyrans ylmethyl, THP trtrahydropyranyl, cyclobutyl, allyl group, proyl or thiazolyl.
One embodiment of the invention provide formula I, and wherein R13 represents (C 1-C 4) alkyl, cyano group or F.
One embodiment of the invention provide above formula I, and wherein R13 represents (C 1-C 4) alkyl, cyano group, halogen ,=O ,-ORa Huo – COORf.
One embodiment of the invention provide above formula I, and wherein R13 represents methyl, cyano group, F ,=O ,-OCH 3or-COOC (CH 3) 3.
One embodiment of the invention provide formula I, and wherein R11 or R12 represents hydrogen independently.
One embodiment of the invention provide formula I, and described compound is:
Ingenol 3-(5-methyl-3-phenyl-different azoles-4-manthanoate) or
Ingenol 3-(5-methyl-3-(the fluoro-phenyl of the chloro-6-of 2-)-different azoles-4-manthanoate) or
Ingenol 3-(1S-camphane acid esters) or
Ingenol 3-(3-Phenyltriazole-4-manthanoate) or
Ingenol 3-(2-phenylpyrazole-3-manthanoate) or
Ingenol 3-(1-methyl-benzdiazole-3-formic acid ester) or
Ingenol 3-(3-ethyl-5-methyl-different azoles-4-manthanoate) or
Ingenol 3-(3-methyl-5-methyl-different azoles-4-manthanoate) or
Ingenol 3-(1-skatole-3-manthanoate) or
Ingenol 3-(3-tolylthiophene-2-manthanoate) or
(5-phenyl is different for ingenol 3- azoles-3-manthanoate) or
Ingenol 3-(N-Ethyl-carbamic acid ester) or
Ingenol 3-(N, N-dimethyl-amino manthanoate) or
Ingenol 3-(morpholine-4-manthanoate) or
Ingenol 3-(tetramethyleneimine-1-manthanoate) or
Ingenol 3-(N-Methyl-N-phenyl-carbamate) or
Ingenol 3-(N, N-Diethyl-carbamic acid ester) or
Ingenol 3-(piperidines-1-manthanoate) or
Ingenol 3-(N-Benzyl-N-methyl-carbamate) or
Ingenol 3-(N-cyclohexyl-N-methyl-carbamate) or
Ingenol 3-(N-cyclohexyl-carbamate) or
Ingenol 3-(N-phenyl-carbamate) or
Ingenol 3-(N-(indane-1-base)-carbamate) or
Ingenol 3-(3,3-DimethYI-pineridin-1-manthanoate) or
Ingenol 3-(N-methyl-N-naphthane-1-base-carbamate) or
Ingenol 3-(N-(2-cyano group-1-methyl-ethyl)-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-methyl-N-((S)-1-styroyl)-carbamate) or
Ingenol 3-(N-methyl-N-(Cvclopropvlmethvl)-carbamate) or
Ingenol 3-(isoquinoline 99.9-1-manthanoate) or
Ingenol 3-(quinoline-4-manthanoate) or
Ingenol 3-(cinnolines-4-manthanoate) or
Ingenol 3-(3-phenylimidazole-4-manthanoate) or
Ingenol 3-(5-phenyl azoles-4-manthanoate) or
Ingenol 3-(1,2-benzo azoles-3-manthanoate) or
Ingenol 3-(3-sec.-propyl-5-methyl-different azoles-4-manthanoate) or
Ingenol 3-(3-(2-p-methoxy-phenyl)-5-methyl-different azoles-4-manthanoate) or
Ingenol 3-(the bromo-2-methyl pyrazole of 4--3-manthanoate) or
Ingenol 3-(4-bromo-2-ethyl-pyrazoles-3-manthanoate) or
Ingenol 3-(4-chloro-2-methyl-pyrazoles-3-manthanoate) or
Ingenol 3-(5-bromo pyrimi piperidine-4-manthanoate) or
Ingenol 3-(3-bromopyridine-2-manthanoate) or
Ingenol 3-(5-methylthiazol-4-manthanoate) or
Ingenol 3-(the chloro-1-methyl pyrazole of 4--3-manthanoate) or
Ingenol 3-(2,4-dimethylthiazole-5-manthanoate) or
Ingenol 3-(2,5-dimethyl azoles-4-manthanoate) or
Ingenol 3-(2,4-dimethyl furan-3-manthanoate) or
(3,5-diethyl is different for ingenol 3- azoles-4-manthanoate) or
Ingenol 3-(N-(the fluoro-phenyl of 3-)-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-(2,5-dimethyl pyrazole-3-base)-N-Methyl-carbamic acid ester) or
Ingenol 3-(1H-indoles-7-manthanoate) or
Ingenol 3-(the 2-tertiary butyl-5-methyl pyrazole-3-manthanoate) or
Ingenol 3-(the 5-tertiary butyl-2-methyl pyrazole-3-manthanoate) or
Ingenol 3-(6-Methylimidazole is [2,1-b] thiazole-5-manthanoate also) or
Ingenol 3-(glyoxal ethyline is [1,2-a] Nicotinicum Acidum ester also) or
Ingenol 3-(2,4,5-trimethylammonium furans-3-manthanoate) or
Ingenol 3-(3 methyl thiophene-2-manthanoate) or
Ingenol 3-(2-methyl-4-(piperidino) pyrazoles-3-manthanoate) or
Ingenol 3-(the chloro-5-sec.-propyl-4-thiazolecarboxylic acid ester of 2-) or
Ingenol 3-(chloro-2, the 5-Dimethyl-pyrazol-3-manthanoate of 4-) or
Ingenol 3-(1,2,4-trimethylammonium pyrroles-3-manthanoate) or
Ingenol 3-(1,3,5-trimethylammonium pyrroles-2-manthanoate) or
Ingenol 3-(1-ethyl-3,5-dimethyl pyrrole-2-manthanoate) or
Ingenol 3-(1-t-butyloxycarbonyl-3,3-dimethyl pyrrolidine-2-manthanoate) or
Ingenol 3-((2S)-1-Phenylpyrrolidine-2-manthanoate) or
Ingenol 3-(1-sec.-propyl-3,5-Dimethyl-pyrazol-4-manthanoate) or
Ingenol 3-(5-ethyl-3-sec.-propyl-different azoles-4-manthanoate) or
Ingenol 3-(2-methyl-benzdiazole-3-formic acid ester) or
Ingenol 3-(5-methyl-3-the tertiary butyl-different azoles-4-manthanoate) or
Ingenol 3-(2-methyl-3-oxo-4-oxaspiro [4.5]-1-in last of the ten Heavenly stems alkene-1-manthanoate) or
Ingenol 3-(the 1-tertiary butyl-3,5-Dimethyl-pyrazol-4-manthanoate) or
Ingenol 3-(3,5-dimethyl isothiazole-4-manthanoate) or
Ingenol 3-(the iodo-3-methyl-isothiazol of 5--4-manthanoate) or
Ingenol 3-(4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-manthanoate) or
Ingenol 3-(4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-manthanoate) or
Ingenol 3-(2-methyl-4-(4-methylsulfonyl phenyl) pyrazoles-3-manthanoate) or
Ingenol 3-(2-methyl 4-phenyl-pyrazoles-3-manthanoate) or
Ingenol 3-(3,5-dimethyl-1-phenyl-pyrazole-4-manthanoate) or
Ingenol 3-(1,5-dimethyl-3-phenyl-pyrazole-4-manthanoate) or
Ingenol 3-(1-benzyl-3,5-Dimethyl-pyrazol-4-manthanoate) or
Ingenol 3-(3,5-dimethyl-1-(tetrahydropyran-4-base methyl) pyrazoles-4-manthanoate) or
Ingenol 3-(4-methyl-2-oxo-3H-thiazole-5-manthanoate) or
Ingenol 3-(2-methyl-4,5,6,7-tetrahydrochysene indazole-3-manthanoate) or
Ingenol 3-(1,2-dimethyl indole-3-manthanoate) or
Ingenol 3-(5-methoxyl group-1,2-dimethyl-indol-3-manthanoate) or
Ingenol 3-(1,3,5-trimethylpyrazol-4-manthanoate) or
Ingenol 3-(4-methyl isophthalic acid, 2,5- diazole-3-manthanoate) or
Ingenol 3-(2-methoxyl group-4-methyl-thiazole-5-manthanoate) or
(4,5-dimethyl is different for ingenol 3- azoles-3-manthanoate) or
Ingenol 3-(the bromo-1-methyl pyrazole of 4--3-manthanoate) or
Ingenol 3-(1,3-dimethyl indole-2-manthanoate) or
Ingenol 3-(5-methoxyl group-1,3-dimethyl-indol-2-manthanoate) or
Ingenol 3-(2,4-dimethyl-6-oxo-pyrans-3-manthanoate) or
Ingenol 3-(1-methyl-3-phenyl-indole-2-manthanoate) or
(3-methyl-5-(trifluoromethyl) is different for ingenol 3- azoles-4-manthanoate) or
Ingenol 3-(1,3-dimethyl pyrrole-2-manthanoate) or
Ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl) pyrazoles-4-manthanoate) or
Ingenol 3-(1-cyclopropyl-2,5-Dimethyl-pyrrol-3-manthanoate) or
Ingenol 3-(1,2,5-trimethylammonium pyrroles-3-manthanoate) or
Ingenol 3-(2,4-dimethyl-1H-pyrroles-3-manthanoate) or
Ingenol 3-(1-methylpyrrole-2-manthanoate) or
Ingenol 3-(4-methyl isophthalic acid H-pyrroles-2-manthanoate) or
Ingenol 3-(1,5-dimethyl pyrrole-2-manthanoate) or
Ingenol 3-(3-methyl isophthalic acid H-pyrroles-2-manthanoate) or
Ingenol 3-(1-cyclopropyl pyrroles-2-manthanoate) or
Ingenol 3-(1-ethyl-2,4-Dimethyl-pyrrol-3-manthanoate) or
Ingenol 3-(1-allyl group-2,4-Dimethyl-pyrrol-3-manthanoate) or
Ingenol 3-(1-(Cvclopropvlmethvl)-2,4-Dimethyl-pyrrol-3-manthanoate) or
Ingenol 3-(1-(2-methoxy ethyl)-2,4-Dimethyl-pyrrol-3-manthanoate) or
((3,5-dimethyl is different for N-for ingenol 3- azoles-4-base)-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-(1,5-dimethyl pyrazole-3-base)-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-cyclopentyl-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-cyclopropyl-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-methyl-N-(2-pyridyl)-carbamate) or
Ingenol 3-(4-oxo-2,3-dihydroquinoline-1-manthanoate) or
Ingenol 3-(3,4-dihydro-2H-quinoline-1-manthanoate) or
Ingenol 3-(indoline-1-manthanoate) or
Ingenol 3-(azepan-1-manthanoate) or
Ingenol 3-(N-(the chloro-phenyl of 4-)-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-(the fluoro-phenyl of 4-)-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-methyl-N-(2-methoxyl group-phenyl)-carbamate) or
Ingenol 3-(N-methyl-N-(2-methylphenyl)-carbamate) or
Ingenol 3-(3-oxo-2,4-dihydro-quinoxaline-1-manthanoate) or
Ingenol 3-(N-ethyl, N-phenyl-carbamate) or
Ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) or
Ingenol 3-(3-azabicyclic [3.2.2] nonane-3-manthanoate) or
Ingenol 3-(2,3-dihydro-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate) or
Ingenol 3-(N-(the fluoro-phenyl of 2-)-N-Methyl-carbamic acid ester) or
Ingenol 3-(3-methyl-2,3-dihydros-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate) or
Ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) (isomer A) or
Ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) (isomer B) or
Ingenol 3-(N-methyl-N-(N-(t-butyloxycarbonyl)-4-piperidyl)-carbamate) or
Ingenol 3-(N-methyl-N-(3-methylphenyl)-carbamate) or
Ingenol 3-(3,4-dihydro-2H-quinoxaline-1-manthanoate) or
Ingenol 3-(isoindoline-2-manthanoate) or
Ingenol 3-(N-methyl-N-(tetrahydropyran-4-base methyl)-carbamate) or
Ingenol 3-(N-methyl-N-(tetrahydropyran-4-base)-carbamate) or
Ingenol 3-(N-methyl-N-(3-methoxyl group-phenyl)-carbamate) or
Ingenol 3-(N-cyclobutyl-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-allyl group-N-Methyl-carbamic acid ester) or
Ingenol 3-(N-methyl-N-Propargyl-carbamate) or
Ingenol 3-(N-methyl-N-(4-methylthiazol-2-base)-carbamate) or
Ingenol 3-(N-(4-cvano-phenyl)-N-Methyl-carbamic acid ester).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(N-Methyl-N-phenyl-carbamate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(N-(the fluoro-phenyl of 3-)-N-Methyl-carbamic acid ester).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(3-ethyl-5-methyl-different azoles-4-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(2,4-dimethyl furan-3-manthanoate).
One embodiment of the invention provide formula I, and described compound is that (3,5-diethyl is different for ingenol 3- azoles-4-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(2,4,5-trimethylammonium furans-3-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(2-methyl 4-phenyl-pyrazoles-3-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(3 methyl thiophene-2-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(indoline-1-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(5-methyl-3-phenyl-different azoles-4-manthanoate).
One embodiment of the invention provide formula I, and described compound is ingenol 3-(tetramethyleneimine-1-manthanoate).
Definition
In the present context, term " (C a-C b) alkyl " (wherein a and b is integer) refer to the straight or branched alkyl with a to b carbon atom, such as 1-7 or 1-6, such as 1-4 or 1-3 carbon atom.Therefore, when a is 1 and b is 7, such as this term comprise methyl, ethyl, n-propyl group, sec.-propyl, n-butyl, isobutyl-, the second month in a season-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl and heptyl.
Term " carbocyclic ring " refer to the list that is up to 13 annular atoms, such as 3-13 or 3-10 annular atomses-, two-or three cyclic groups, all annular atomses are all carbon, and comprise aryl, cycloalkyl and cycloalkenyl group.
Term " cycloalkyl " refer to comprise 3-13 carbon atom, such as 3-10, such as 3-8, a such as 3-5 carbon atom list-, two-or three ring filling naphthenic hydrocarbon groups, and comprise such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two rings [2.2.1] heptane base and adamantyl.
Term " (C a-C b) alkenyl " and (wherein a and b is integer) refer to have a to b carbon atom, such as 2-7 or 2-6 or 2-4 or 2-3 carbon atom list-, two-or three-unsaturated straight or branched alkenyl.Therefore, when a is 1 and b is 7, such as this term comprises vinyl, allyl group, propenyl; 1-, 2-or 3-butenyl; 1-, 2-, 3-or 4-pentenyl; 1-, 2-, 3-, 4-or 5-hexenyl.
Term " cycloalkenyl group " refer to comprise 3-13 carbon atom, such as 3-10, such as 3-8, a such as 3-5 carbon atom list-, two-or triunsaturated non aromatic cyclic alkyl, comprise polycyclic moiety, and comprise such as cyclopropenyl radical, cyclobutene base, cyclopentenyl or cyclohexenyl.
Term " (C a-C b) alkynyl " (wherein a and b is integer) refer to and comprise the straight or branched alkyl that 1-2 C-C triple bond has a to b carbon atom, such as 2-7 or 2-6 or 2-4 or 2-3 carbon atom.Therefore, when a is 1 and b is 7, such as this term comprises ethynyl, proyl, butynyl, pentynyl or hexin base.
Term " heterocycle " refers to and comprises the carbon ring group heteroatomic defined above that 1-4 is selected from O, N or S, and comprises heteroaryl, Heterocyclylalkyl and heterocycloalkenyl.
What term " Heterocyclylalkyl " referred to optionally condensed with carbocyclic ring comprises the heteroatomic cycloalkyl that 1-4 is selected from O, N or S, comprises polycyclic moiety.
Term " Heterocyclylalkyl " also refers to the group of naphthene base optionally condensed with carbocyclic ring (comprising aryl), comprises polycyclic moiety, condition be tie point by non-aromatic ring, this group of naphthene base comprises the heteroatoms that 1-4 to be selected from O, N or S.Such as, piperazinyl, tetrahydrofuran base, pyrrolidyl, dioxolanyl, morpholinyl, imidazolidyl, piperidyl, 5-oxabicyclo [2.2.2] octane, dihydroquinoline base, indolinyl, dihydro-quinoxaline base, oxo-thiazol base, oxo-pyranyl, azepan base, azabicyclic [3.2.2] nonyl, benzo piperazine base, quinoxalinyl, dihydro-iso indolyl, indolinyl or THP trtrahydropyranyl, particularly tetrahydrofuran base, pyrrolidyl, dioxolanyl, morpholinyl, imidazolidyl, piperidyl or 5-oxabicyclo [2.2.2] octane.
What term " heterocycloalkenyl " referred to optionally condensed with carbocyclic ring comprises the cycloalkenyl groups heteroatomic defined above that 1-4 is selected from O, N or S, comprises polycyclic moiety, such as dihydro pyranyl, dihydro-thiazolyl.
Term " aryl " refers to the aromatic carbocyclic group comprising 6-10 carbon atom, particularly phenyl, and has the carbocyclic ring optionally condensed of at least 1 aromatic ring, particularly 5-or 6-ring.Therefore, this term comprises such as 1,2,3,4-tetrahydro-naphthalenyl, phenyl, naphthyl, indenyl or indanyl, particularly phenyl, naphthyl, indenyl or indanyl.
Term " heteroaryl " refer to optionally with carbocyclic ring or heterocyclic fused heterocyclic aromatic ring groups, it comprises heteroatoms and 1-12 carbon atom that 1-4 is selected from O, S and N, such as 1-4 heteroatoms and 1-6 carbon atom, particularly there is 1-4 heteroatomic 5-or 6-ring, or have 1-4 heteroatomic two rings optionally condensed, and wherein at least 1 ring is aromatic.This term comprise such as pyridyl, quinolyl, isoquinolyl, indyl, tetrazyl, furyl, thiazolyl, imidazolyl, imidazo [1,2-a] pyrimidyl, pyrryl, pyrazolyl, azoles base, different azoles base, di azoly, 1,2,4-triazolyl, thienyl, pyrazinyl, pyrimidyl, 1,2,3-triazoles base, isothiazolyl, imidazo [2,1-b] thiazolyl, benzimidazolyl-, benzofuryl, benzofuryl, benzothienyl, benzothiazolyl, benzo azoles base, indazolyl, cinnolines base, 1,2-benzo azoles base, Imidazothiazole base, imidazopyridyl, pyrryl, isothiazolyl, tetrahydrochysene indazole base, di azoly, particularly pyridyl, quinolyl, isoquinolyl, indyl, tetrazyl, furyl, thiazolyl, imidazolyl, imidazo [1,2-a] pyrimidyl, pyrryl, pyrazolyl, azoles base, different azoles base, di azoly, 1,2,4-triazolyl, thienyl, pyrazinyl, pyrimidyl, 1,2,3-triazoles base, isothiazolyl, imidazo [2,1-b] thiazolyl, benzimidazolyl-, benzofuryl, benzofuryl, benzothienyl, benzothiazolyl, benzo azoles base, indazolyl, or particularly pyridyl, quinolyl, isoquinolyl, indyl, tetrazyl, furyl, thiazolyl, imidazolyl, imidazo [1,2-a] pyrimidyl, pyrryl, pyrazolyl, azoles base, different azoles base, di azoly, 1,2,4-triazolyl, thienyl, pyrazinyl, pyrimidyl, 1,2,3-triazoles base, isothiazolyl, imidazo [2,1-b] thiazolyl, benzimidazolyl-, benzofuryl, benzofuryl, benzothienyl, benzothiazolyl, benzo azoles base, indazolyl, cinnolines base, 1,2-benzo azoles base.
Term " halogen " means the substituting group from the periodic table of elements the 7th main group, preferred fluorine, chlorine and bromine.
Term " alkoxyl group " means the group of Shi – OR, and wherein R is above shown alkyl, such as methoxyl group, oxyethyl group, n-propoxy-, isopropoxy, butoxy etc.
Term " halogenated alkoxy " means Shi – O-R-X (1-3)group, wherein R be above shown in alkyl and X be above shown in halogen, such as trifluoromethoxy.
Term hydroxyalkyl means the primary, secondary or tertiary group of formula-R-OH, and wherein R is above shown alkyl, such as hydroxymethyl or hydroxyethyl.
Term cyanoalkyl means the primary, secondary or tertiary group of formula-R-CN, and wherein R is above shown alkyl, such as cyano methyl or cyano ethyl.
Term haloalkyl means formula-R-X (1-3)primary, secondary or tertiary group, wherein R be above shown in alkyl and X be above shown in halogen, such as trifluoromethyl, 2,2,2-trifluoroethyls or difluoromethyl.
When two or more term as defined above is combinationally used, such as arylalkyl, heteroarylalkyl, cycloalkylalkyl etc., should be understood that the substituting group on the group mentioned after the group first mentioned is, the tie point be wherein connected with another part of molecule is on group below.
Term " alkoxyalkyl " means alkyl group defined above, and this group is replaced by alkoxy base defined above, that is ,-R-O-R, and wherein each R is above shown identical or different alkyl, such as methoxymethyl, ethoxyl methyl.
Term " cycloalkylalkyl " means the group of formula-R ’ – cycloalkyl, and wherein R ' is alkyl defined above, such as
Term " cycloalkenyl alkyl " means the group of formula-R ’ – cycloalkenyl group, and wherein R ' is alkyl defined above, such as
Term " arylalkyl " means the group of Shi – R ’ – Ar, and wherein R ' is alkyl defined above and Ar is aryl defined above, such as
Term " heteroarylalkyl " means the group of Shi – R '-Het, and wherein R ' is alkyl defined above and Het is assorted aryl defined above, such as
Term " hetercycloalkylalkyl " means the group of formula-R ’ – Heterocyclylalkyl, and wherein R ' is alkyl defined above, such as
Term " heterocycloalkenyl alkyl " means the group of formula-R ’ – heterocycloalkenyl, and wherein R ' is alkyl defined above, such as
Term alkyl-cycloalkyl means the group of Shi – cycloalkyl-R ', and wherein R ' is alkyl defined above, such as
Term " alkylcycloalkenyl " means the group of Shi – cycloalkenyl group-R ', and wherein R ' is alkyl defined above, such as
Term " alkylaryl " means the group of Shi – Ar-R ', and wherein R ' is alkyl defined above and Ar is aryl defined above, such as;
Term " miscellaneous alkyl aryl " means the group of Shi – Het-R ', and wherein R ' is alkyl defined above and Het is heteroaryl defined above, such as;
Term " Alkyl cycloheteroalkyl " means the group of Shi – Heterocyclylalkyl-R ', and wherein R ' is alkyl defined above, such as;
Term ' replacement ' for this paper any part means to replace with compatible substituting group.
Term " pharmacologically acceptable salt " means the salt by comprising prepared by the formula I of basic group and suitable inorganic or organic acid reaction, described inorganic or organic acid is such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2, 2-dichloro acetic acid, choline, hexanodioic acid, xitix, L-Aspartic acid, Pidolidone, tetrahydroxyadipic acid, lactic acid, toxilic acid, L MALIC ACID, phthalic acid, citric acid, propionic acid, phenylformic acid, pentanedioic acid, glyconic acid, D-glucuronic acid, methylsulfonic acid, Whitfield's ointment, succsinic acid, propanedioic acid, tartrate, Phenylsulfonic acid, second-1, 2-disulfonic acid, 2-ethylenehydrinsulfonic acid, toluenesulphonic acids, thionamic acid or fumaric acid.The pharmacologically acceptable salt comprising the formula I of acidic-group also by with suitable alkali such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonia or suitable nontoxic amine, such as low-grade alkylamine, such as triethylamine, hydroxy lower alkyl amine, such as 2-hydroxyethyl amine, two-(2-hydroxyethyl)-amine, Cycloalkyl amine, such as dicyclohexylamine or benzyl amine, such as N, N '-dibenzyl-ethylenediamin and dibenzyl amine or L-arginine or 1B react to prepare.
The present invention comprises the prodrug of compound of Formula I further, such as ester class, acetals, ketal class or other derivative, and they carry out bio-transformation in vivo, then show its pharmacological action.
Term " solvate " means the material formed by compound such as formula I and the solvent interaction such as between alcohol, glycerine or water, and wherein said material is solid form.When water is solvent, described material is referred to as hydrate.
Formula I can be direct by concentrating from organic solvent or being obtained by crystallization or recrystallization in the mixture from organic solvent or described solvent and cosolvent in crystalline form, and described cosolvent can be organic or inorganic, such as water.By crystallization with solvent-free form or the isolated in form with solvate such as hydrate substantially.The present invention covers all crystal modification and form and composition thereof.
Term " cancer " is intended to contain skin carcinoma in the context of the present invention, such as non-melanoma skin carcinoma, malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma and rodent cancer.Rodent cancer comprises superficial basal cell carcinoma and nodositas rodent cancer.Squamous cell carcinoma comprises squamous cell carcinoma in situ (bowen's disease), infiltrative type squamous cell carcinoma, cutaneous squamous cell carcinoma, mucous membrane squamous cell carcinoma, head and neck squamous cell carcinoma.The cancer of other type comprises haematol cancer, such as Myeloid cancer, particularly such as acute myeloid leukaemia and chronic myelogenous leukemia; The cancer of prostate gland and bladder, comprises the cancer of cancer, bladder in benign prostate hyperplasia, prostatic epithelium, adenocarcinoma of prostate and renal cell carcinoma.Other cancer comprises AIDS associated cancer, acoustic tumor, adenoid cystic carcinoma, adrenal cortex cancer, agnogenic myeloid metaplasia, alopecia, alveolar soft part sarcoma, anus cancer, angiosarcoma, aplastic anemia, astrocytoma, ataxia telangiectasia, rodent cancer (bcc), bladder cancer, osteocarcinoma, intestinal cancer, brain stem glioma, brain and CNS cancer, mammary cancer, CNS cancer, carcinoid, cervical cancer, the young stage cancer of the brain, young stage cancer, young stage soft tissue sarcoma, chondrosarcoma, choriocarcinoma, colorectal carcinoma, cutaneous T cell lymphoma, dermatofibrosarcoma protuberans, short desmoplastic small circle cell cancer, duct carcinoma, internal secretion cancer, carcinoma of endometrium, ependymoma, the esophageal carcinoma, Ewing's sarcoma, cholangiocarcinoma, cancer eye, ophthalmomelanoma, retinoblastoma, carcinoma of fallopian tube, Fanconi anemia, fibrosarcoma, carcinoma of gallbladder, cancer of the stomach, gastrointestinal cancer, gastrointestinal associated cancers, urogenital cancer, germinocarcinoma, gestational trophoblastic disease, neurospongioma, gynecological cancer, hematologic malignancies, comprises acute myeloid leukaemia, head and neck cancer, hepatocellular carcinoma, hereditary breast cancer, histiocytosis, Hodgkin's disease, human papillomavirus, hydatidiform mole, hypercalcemia, hypopharynx cancer, intraocular melanoma, islet-cell carcinoma, Kaposi's sarcoma, kidney, Langerhans cell histiocytosis, laryngocarcinoma, leiomyosarcoma, li-Fraumeni syndrome, lip cancer, liposarcoma, liver cancer, lung cancer, lymphedema, lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, male breast carcinoma, MRTK, medulloblastoma, mesothelioma, metastatic carcinoma, mouth cancer, multiple endocrine neoplasia, mycosis fungoides, myelodysplastic syndrome, myelomatosis, myeloproliferative diseases, rhinocarcinoma, nasopharyngeal carcinoma, the nephroblastoma, neuroblastoma, neurofibromatosis, Nijmegen breakage syndrome, non-small cell lung cancer (nsclc), cancer eye, the esophageal carcinoma, oral carcinoma, oropharynx cancer, osteosarcoma, ostomy ovarian cancer (ostomyovariancancer), carcinoma of the pancreas, paranasal sinus cancer, parathyroid carcinoma, carcinoma of parotid gland, penile cancer, peripheral nerve ectoderm cancer, hypophysis cancer, polycythemia vera, prostate cancer, rare cancer and associated disorders, retinoblastoma, rhabdosarcoma, rothmund-Thomson syndrome, salivary gland carcinoma, sarcoma, schwannoma, Sezary syndrome, small cell lung cancer (sclc), small bowel cancer, soft tissue sarcoma, spinal cord cancer, cancer of the stomach, synovial sarcoma, testicular cancer, thymic carcinoma, thyroid cancer, transitional cell carcinoma (bladder), transitional cell carcinoma (kidney-renal plevis-/-ureter), trophoderm cancer, urethral cancer, urinary system cancer, uroplakins, sarcoma of uterus, uterus carcinoma, carcinoma of vagina, carcinoma vulvae, macroglobulinemia Waldenstron and Willms cancer (Wilms'Cancer).The described solid carcinoma using method of the present invention to treat can be primary lesion or can be the consequence that primary carcinoma shifts.In addition, if described solid carcinoma is the transfer of primary carcinoma, then described primary carcinoma can be former solid carcinoma as described above or can be the primary carcinoma of diffusion.
In one embodiment of the invention, " cancer " is skin carcinoma.
In embodiments of the invention, skin carcinoma is that non-melanoma skin cancer, malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma, squamous cell carcinoma, rodent cancer are as superficial basal cell carcinoma or nodositas rodent cancer.
In the context of the present invention; phrase " physiological conditions relevant with hyperplasia or tumour or disease " comprises following illness or disease, such as cutaneous wart, comprise verruca vulgaris (Verrucavulgaris), plantar wart (sole of the foot wart) and verruca plana (Verrucaplana); Genital warts (pointed condyloma), pyogenic granuloma, vascular tumor, scleroderma; Cancer and precancerous lesion be actinic keratosis, squamous cell carcinoma such as, comprises squamous cell carcinoma in situ (bowen's disease), infiltrative type squamous cell carcinoma, cutaneous squamous cell carcinoma, mucous membrane squamous cell carcinoma, head and neck squamous cell carcinoma; Rodent cancer, comprises superficial basal cell carcinoma and nodositas rodent cancer; Bladder cancer, malignant freckle, cervical dysplasia, vulva dysplasia and anus dysplasia, primary in situ melanoma, head and neck cancer, the cutaneous metastatic of any cancer, Kaposi's sarcoma, keratoacanthoma, Merkel cell tumour, prostate cancer, mycosis fungoides, intraepithelial neoplasia, comprise anus, uterine neck, breast duct, oral cavity, crissum, prostate gland, penis, vagina and vulva intraepithelial neoplasia.
In the context of the present invention, term " beauty treatment indication " comprises the skin of indication such as light injury, seborrheic keratosis, scar, keloid, chloasma, civatte's disease, removal are tatooed, hemorrhoid and skin are gone to live in the household of one's in-laws on getting married.
In the context of the present invention, to be intended to contain microgroove, wrinkle and UV-aging for term " skin of light injury ".Aging increase or the atrophy of epidermis often showing as epidermal thickness of UV, and show as solar elastosis the most significantly, the material namely containing elastin is accumulated in the below of next-door neighbour's dermal-epidermal junction.Collagen and spandex fiber division are disintegrated.In beauty treatment level, erythrosis and/or thickening can be observed, thus cause leather shape outward appearance, skin fragility and irregular pigmentation, the colour of skin and flexibility missing and wrinkle, drying, freckle and gash to be formed.
In the context of the present invention, term " virus infection " is intended to contain the HPV infection causing forming wart on health such as skin, sexual organ and mouth.HPV refers to human papillomavirus.Other virus is selected from adenovirus, papovavirus, simplexvirus (such as hsv) varicella zoster virus, Epstein-Barr virus, CMV virus, poxvirus (such as variola virus) vaccinia virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, rhinovirus, poliovirus, rubella virus, arboviruses, rabies virus, influenza A virus and Influenza B virus, Measles virus, mumps virus and HIV, HTLVI and II.In one embodiment of the invention, HPV infects and relates to verruca vulgaris or Genital warts.
In the context of the present invention, term " bacteriological infection " be intended to contain protokaryon with the bacteriological infection of eucaryon and gram positive bacterium and gram negative bacterium and gram-variable bacteria and intracellular bacterium.The example of bacterium comprises treponema (Treponema), Borrelia (Borrelia), Neisseria (Neisseria), Legio (Legionella), Bordetella (Bordetella), Escherichia (Escherichia), salmonella (Salmonella), Shigella (Shigella), Klebsiella (Klebsiella), Yersinia (Yersinia), Vibrio (Vibrio), hemophilus (Hemophilus), Dermacentroxenus (Rickettsia), chlamydiaceae (Chlamydia), Mycoplasma (Mycoplasma), Staphylococcus (Staphylococcus), streptococcus (Streptococcus), bacillus (Bacillus), fusobacterium (Clostridium), Corynebacterium (Corynebacterium), propiono-bacterium (Proprionibacterium), Mycobacterium (Mycobacterium), Ureaplasma urealyticum (Ureaplasma) and Listerial (Listeria).Particularly following species: Treponoma palladium (Treponemapallidum), B. burgdorferi (BorreliaBurgdorferi), gonococcus (Neisseriagonorrhoea), invade lung legionella (Legionellapneumophila), Bordetella pertussis (Bordetellapertussis), colon bacillus (Escherichiacoli), Corynebacterium diphtheriae (Salmonellatyphi), bacillus typhi murium (salmonellatyphimurium), shigella dysenteriae (Shigelladysenteriae), pneumobacillus (Klebsiellapneumoniae), plague bacillus (Yersiniapestis), vibrio cholerae (Vibriocholerae), hemophilus influenzae (Hemophilusinfluenza), Rickettsia rickettsii (Rickettsiarickettsii), chlamydia trachomatis (Chlamydiatrachomatis), mycoplasma pneumoniae (M ycoplasmapneumonia), streptococcus aureus (Staphylococcusaureus), streptococcus pneumoniae (Streptococcuspneumoniae), streptococcus pyogenes (Streptococcuspyogenes), anthrax bacillus (Bacillusanthracis), Clostridium botulinum (Clostridiumbotulinum), clostridium tetani (Clostridiumtetani), clostridium perfringens (clostridiumperfringens), diphtheria corynebacterium (Corynebacteriumdiphteriae), sore blister bar bacterium (Proprionibacteriumacne), mycobacterium tuberculosis (Mycobacteriumtuberculosis), Mycobacterium leprae (Mycobacteriumleprae) and Listeria monocytogenes (Listeriaremonocytogenes).Lower eukaryotes comprises yeast and fungi such as Pneumocystisnerinii, Candida albicans (Candidaalbicans), Eurotium (Aspergillus), Histoplasma capsulatum (Histoplasmacapsulatum), Blastomyces dermatitidis (Blastomycesdermatitidis), Cryptococcus neoformans (Cryptococcusneoformans), Trichophyton (Trichophyton) and Microsporon (Microsporum).Complicated eukaryote comprises worm, insect, spider, nematode, aemobe, entamoeba historlytica (Entamoebahistolytica), giardia lamblia (Giardialamblia), Trichomonas vaginalis (Trichonomonasvaginalis), Bu Shi castellanella gambiense (Trypanosomabruceigembiense), schizotrypanum cruzi (Trypanosomacruzi), balantidium coli (Blantidiumcoli), toxoplasma gondii (Toxoplasmagondii), Cryptosporidium (Cryptosporidium) or leishmaniasis (Leishmania).
In the context of the present invention, term " wound healing " means: reduce in wound and scar reduce or minimize scar tissue or improve cosmetology or functional outcome, wherein said wound is skin, chronic or such as relevant to diabetes wound, and comprise cut wound and lacerated wound, operative incision, stab, scratch, scratch, crush injury, fray, friction wound, chronic wound, ulcer, heat effect wound, chemical trauma, the wound that pathogen infection causes, skin graft/transplantation donor and receptor site, immunne response situation, mouth wound, stomach or intestines wound, impaired cartilage or bone, amputation side and corneal injury.
The compounds of this invention expection is used for the treatment of the treatment of skin of cancer, actinic keratosis, seborrheic keratosis, virus infection, bacteriological infection, wound healing and light injury.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of superficial basal cell carcinoma (BCC), nodositas BCC, squamous cell carcinoma or squamous cell carcinoma in situ (SCCIS).
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of actinic keratosis.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of seborrheic keratosis.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of the skin of light injury.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of and infects by HPV the pathology caused.
In one embodiment of the invention, this pathology is verruca vulgaris or Genital warts.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of squamous cell carcinoma in situ or infiltrative type squamous cell carcinoma.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of cutaneous squamous cell carcinoma, mucous membrane squamous cell carcinoma or head and neck squamous cell carcinoma.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of superficial basal cell carcinoma or nodositas rodent cancer.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of cutaneous wart or Genital warts.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of verruca vulgaris, plantar wart and verruca plana.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of malignant freckle.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of tumor-like lesion or Vulvar intraepithelial neoplasia in cervical intraepithelial neoplasia (CIN), anoderm.
In one embodiment of the invention, the compounds of this invention expection is used for the treatment of acute myeloid leukaemia.
In one embodiment, the invention provides the method for skin of Therapeutic cancer, actinic keratosis, seborrheic keratosis, virus infection, bacteriological infection, wound healing and treatment light injury, the individuality that the method comprises to needs treatment uses formula I.
In one embodiment, the invention provides the method for the treatment of actinic keratosis, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the method for the treatment of seborrheic keratosis, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the method for the skin for the treatment of light injury, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the pathology caused is infected in treatment method by HPV, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the method for the treatment of verruca vulgaris or Genital warts, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the method for the treatment of cutaneous squamous cell carcinoma, mucous membrane squamous cell carcinoma or head and neck squamous cell carcinoma, the method comprises the individuality for the treatment of to needs and uses above formula I.
In one embodiment, the invention provides the method for the treatment of verruca vulgaris, plantar wart and verruca plana, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the method for the treatment of malignant freckle, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the method for tumor-like lesion or Vulvar intraepithelial neoplasia in treatment cervical intraepithelial neoplasia (CIN), anoderm, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the purposes of above formula I in the pharmaceutical composition having the disease of response, illness or situation for the preparation for the treatment of or the stimulation that improves centering granulocyte oxidative burst.
In one embodiment, the invention provides above formula I for the preparation for the treatment of or improve stimulation that Human Keratinocytes IL-8 discharges and have purposes in the pharmaceutical composition of the disease of response, illness or situation.
In one embodiment, the invention provides above formula I for the preparation for the treatment of or improve the purposes in the pharmaceutical composition of the necrosis induced disease, illness or the situation that have a response.
In one embodiment, the invention provides prevention, treatment, improve or prevent the stimulation of centering granulocyte oxidative burst to have the physiological conditions of response or the method for disease, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides prevention, treatment, improve or prevent the stimulation of Human Keratinocytes IL-8 release to have the physiological conditions of response or the method for disease, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides prevention, treatment, improve or prevent have the physiological conditions of response or the method for disease to necrosis induced, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides the above formula I that the stimulation being used for the treatment of or improving centering granulocyte oxidative burst has the disease of response, illness or situation.
In one embodiment, the invention provides the above formula I that the stimulation being used for the treatment of or improving Human Keratinocytes IL-8 release has the disease of response, illness or situation.
In one embodiment, the invention provides and be used for the treatment of or improve the necrosis induced above formula I having the disease of response, illness or situation.
In one embodiment, the invention provides the method for the treatment of acute myeloid leukaemia, the individuality that the method comprises to needs treatment uses above formula I.
In one embodiment, the invention provides and be used for the treatment of, prevent, improve or prevent and the skin of actinic keratosis, seborrheic keratosis, cancer, light injury or the formula I being infected the relevant physiological conditions of the pathology that causes or disease by HPV.
In one embodiment, the invention provides formula I for the preparation for the treatment of, improve or physiological conditions that prevention is relevant with the pathology that the skin of actinic keratosis, seborrheic keratosis, cancer, light injury or infected by HPV causes or disease medicine in purposes.
In one embodiment, the invention provides prevention, treatment, improve or prevention and the skin of actinic keratosis, seborrheic keratosis, cancer, light injury or infected the method for the relevant physiological conditions of the pathology that causes or disease by HPV, the method comprises treats individuality to needs and uses formula I.
pharmaceutical composition
For the application in treatment, the form of the compounds of this invention normally pharmaceutical composition.Therefore the present invention relates to the pharmaceutical composition of contained I and pharmaceutically acceptable vehicle or carrier.Vehicle must be " acceptable " in compatible with other composition of composition and harmless to its recipient meaning.
Pharmaceutical composition of the present invention can be unit dosage such as tablet, pill, capsule, powder, granula, elixir, syrup, emulsion, injection, suppository or Parenteral solutions or suspension; For oral, parenteral, through eye, through skin, intraarticular, locally, in lung, nose, oral cavity or rectal administration or be such as disclosed in Remington:TheScienceandPracticeofPharmacy with any alternate manner of the preparation being applicable to the compounds of this invention and according to the way of generally acknowledging, 21st edition, those mode administrations of 2000, LippincottWilliams & Wilkins.
For oral administration in the form of tablets or capsules, formula I suitably can be mixed mutually with oral, nontoxic pharmaceutically acceptable carrier such as ethanol, glycerine, water etc.In addition, also can as one sees fit suitable binding agent, lubricant, disintegrating agent, correctives and tinting material be joined in mixture.Suitable binding agent comprises such as lactose, glucose, starch, gelatin, gum arabic, tragakanta, sodiun alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax etc.Lubricant comprises such as sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Disintegrating agent comprises such as starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.Other vehicle for capsule comprises polyoxyethylene glycol or lipid.
For the preparation of solids composition such as tablet, the active compound of formula I is mixed with one or more vehicle, such as above-described these and other pharmaceutical diluents such as aqueous phase with the solid preformulation composite of the homogenous mixts of obtained contained I.Term " homogeneity " should be understood to and refers to and formula I disperseed equably in whole composition, thus said composition easily can be subdivided into the unit dosage such as tablet or capsule of equivalence.
In dosage unit form, can by compound every day with suitable doses at intervals one or many, but this depends on the situation of patient usually, and according to the prescription that doctor provides.Easily, the dose unit of preparation comprises 0.01mg to 200mg, preferably 0.01mg to 20mg, such as 0.01-5mg formula I.
The optimal dose of the compounds of this invention will depend on the other factors that age of patient and situation, the severity of disease to be treated and medical practitioner are known especially.By compound according to different dosage regimens, such as with every day or be weekly that interval is oral, parenteral or topical.Usually, single dose is in the scope of 0.01 to 200mg/kg body weight.Can by compound every day with the form administration of bolus (that is, by whole per daily dose single administration) or with twice or repeatedly divided dose administration.
If treatment relates to use another kind of therapeutical active compound, for the useful dosage of described compound, suggestion is with reference to Goodman & Gilman ' sThePharmacologicalBasisofTherapeutics, 9th edition, J.G.Hardman and L.E.Limbird (Eds.), McGraw-Hill1995.The administration of the compounds of this invention and one or more other active compounds can or be carried out successively simultaneously.
Liquid preparation for the oral of the compounds of this invention or parenteral admin comprises the such as aqueous solution, syrup, water or oil suspension and the emulsion containing edible oil such as Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil.Synthesis or natural gum such as tragakanta, alginate, gum arabic, dextran, Xylo-Mucine, gelatin, methylcellulose gum or polyvinylpyrrolidone is comprised for the suitable dispersion agent of aqueous suspension or suspending agent.
For parenteral admin such as intramuscular, intraperitoneal, subcutaneous or intravenous injection or instillation, pharmaceutical composition preferably comprises the formula I being dissolved in or being solubilized into suitable acceptable solvent.For parenteral admin, composition of the present invention can comprise aseptic water-based or non-aqueous solvent, particularly water, isotonic saline solution, isotonic glucose solution, buffered soln or be generally used for other solvent of parenteral admin of therapeutic active substance.Composition such as can be filtered by bacteria retaining filter, disinfectant be joined in composition, irradiate composition or heating combination carrys out sterilizing.Or the compounds of this invention can also provide with the form of sterile solid preparations, such as lyophilized powder, be dissolved in sterile vehicle before facing use.Composition for parenteral admin also can comprise conventional additive such as stablizer, buffer reagent or sanitas, such as antioxidant such as methyl hydroxybenzoate etc.
Composition for rectal administration can be mixed with the suppository form of activeconstituents and carrier such as theobroma oil or the form of enema.
The composition being suitable for intra-articular administration can be the form of the sterile aqueous preparations of the activeconstituents of microcrystalline form, such as the form of moisture crystallite suspension.Liposomal formulation or Biodegradable polymeric system also can be used for the activeconstituents presented for intraarticular and administration through eye.
Be suitable for topical, comprise the composition of ophtalmic treatments and comprise liquid or semi-liquid preparations such as liniment, lotion, gelifying agent, application, oil-in-water or water-in-oil emulsion such as creme, ointment or paste; Or solution or suspensoid such as drops.Composition for ophtalmic treatments preferably also comprises cyclodextrin.Be suitable in nose or orally administering or the composition for sucking comprise pulvis, self-propelled and spray agent, such as aerosol and spraying gun.
The skin of people, particularly outer, stratum corneum provide the effective barrier stopping microbial pathogen and noxious chemical infiltration.Although this characteristic of skin is normally useful, but it makes the percutaneous drug delivery of medicine become complicated, because a large amount of (even if not being major part) is coated to the activeconstituents suffered from dermopathic patient skin may can not penetrate into the effective skin layer playing its activity wherein.
Can promote the infiltration of skin by adding penetration enhancers, it comprises Virahol, sulfoxide type, azone class, pyrrolidines, alkanols and glycols.In embodiments of the invention, penetration enhancers comprises DMSO, azone, 2-Pyrrolidone, decyl alcohol and propylene glycol.In one embodiment of the invention, penetration enhancers is Virahol.
In embodiments of the invention, therapeutical active compound is dissolved in suitable solvent.Suitable solvent is glycols, ketone, acetate esters and ether.Confirm that ingenol compound has satisfactory stability in alcohol such as benzylalcohol and Virahol.Usually, ingenol compound prior behavior goes out and has satisfactory stability at a low ph.In embodiments of the invention, the pH of pharmaceutical preparation is lower than 7.In embodiments of the invention, the pH of pharmaceutical preparation is lower than 6.In embodiments of the invention, the pH of pharmaceutical preparation is lower than 4.5.In embodiments of the invention, the pH of pharmaceutical preparation is lower than 4.0.In embodiments of the invention, the pH of pharmaceutical preparation is not less than 2.5 lower than 4.5.In embodiments of the invention, the pH of pharmaceutical preparation is not less than 2.5 lower than 4.0.Preferred pH scope is by comprising suitable buffer reagent to obtain.In one embodiment of the invention, buffer reagent is acetate buffer.In embodiments of the invention, citrate buffer agent is used.In embodiments of the invention, the citrate-phosphate buffer of mixing is used.
In one embodiment, said composition is ointment.Classify according to current FDA, ointment is a kind of semisolid dosage form, its can comprise up to 20 % by weight water and volatile matter and comprise in solvent more than 50 % by weight hydro carbons, wax or polyvalent alcohol.Therefore, according to the present invention, this ointment can be water-in-oil type composition, in this case, can join in the lipophilic ingredients of composition by nanosuspension, make said composition contain up to 10 % by weight or preferably up to 5 % by weight aqueous phase.In addition, said composition can also be comprise to be less than about 2% of composition weight, to be preferably less than the non-aqueous ointment of 1% free-water.
Ointment carrier suitably can comprise that to be selected from by chain length be C 5-60the paraffin and composition thereof of paraffin of hydrocarbon composition.Normally used ointment carrier is Vaseline or White soft paraffin, its by different chain length degree, peak value at about C 40-44hydrocarbon form, or Vaseline and whiteruss are (by the peak value of different chain length degree at C 28-40hydrocarbon composition) mixture.Although Vaseline can provide sealer coat, reduce the result for the treatment of of activeconstituents in the transdermal loss of water and enhancing composition at treated skin surface, but it often has sensation that is greasy and/or that be clamminess, this can continue the quite a long time after coating, and it is not easy to smear.Therefore, preferably use the paraffin be made up of the hydrocarbon of lower chain length, such as by chain length peak value at C 14-16, C 18-22, C 20-22, C 20-26hydrocarbon composition paraffin or its mixture.Find, these paraffin are more acceptable in makeup, because they are not clamminess when applying and/or greasy and more easily smear.Therefore, expect that they can cause the patient compliance improved.The paraffinic hydrocarbon of suitable the type is produced by Sonneborn and is sold with trade(brand)name Sonnecone, such as SonneconeCM, SonneconeDM1, SonneconeDM2 and SonneconeHV.Disclose further in WO08/141078 (being introduced into as a reference at this) and characterize these paraffin.(the hydrocarbon composition of paraffin is determined by gas-chromatography.)
In order to give the viscosity needed for composition, it suitably can comprise lipotropy adhesion-promoting components such as wax.This wax can be by the hydrocarbon of high molecular such as saturated C 35-70the mineral wax of the mixture formation of alkane, such as Microcrystalline Wax.In addition, wax can also be plant or animal wax, such as C 14-32lipid acid and C 14-32the ester of fatty alcohol, such as beeswax.The amount of adhesion-promoting components can change according to the thickening power of composition, but usually in about 1-20 % by weight scope of composition weight.When adhesion-promoting components is micro-crystallization wax, the about 5-15 % by weight, such as about 10 % by weight of its amount normally composition weight.
In order to keep the good physical stability of composition, being separated particularly in order to avoid wherein aqueous phase and fat phase, it preferably comprises the water-in-oil emulsifier that HLB value is 3-8.The example of this emulsifying agent is polyoxyethylene C 8-22alkyl oxide, such as polyoxyethylene stearyl ether, PCE, polyoxyl 10 oleyl ether or polyoxyethylene laurel ether.The 2-10%w/w of the amount of emulsifying agent normally composition weight.
In another embodiment, said composition is the creme comprising the composition similar with ointment, but it normally contains the O/w emulsion of large water gaging.
Said composition also can comprise other composition being generally used for skin preparation, such as antioxidant (such as alpha-tocopherol), sanitas be benzylalcohol, sodium ethylene diamine tetracetate, pigment, skin soothing agents, skin healing agent and skin conditioning agent such as urea, wallantoin or bisabolol such as, see CTFACosmeticIngredientsHandbook, 2nd edition, 1992.In one embodiment of the invention, sanitas is benzylalcohol.
In one embodiment, said composition is gel.Suitable jelling agent comprises the derivative polymkeric substance of water soluble cellulose, such as hydro xyalkyl cellulose polymers.In embodiments of the invention, polymkeric substance is Walocel MT 20.000PV, Natvosol, hydroxypropylcellulose and HPMC.Other jelling agent is that celluloses is as carboxymethyl cellulose, methyl hydroxyl ethyl cellulose and methylcellulose gum, carboxyvinyl polymer such as carbomer and carrageenin.In embodiments of the invention, jelling agent is derivatived cellulose.In embodiments of the invention, Mierocrystalline cellulose is hydroxy alkyl cellulose such as Natvosol.
In one embodiment of the invention, said composition comprises active compound, penetration enhancers, sanitas, jelling agent and pH and is less than 4 and is not less than the buffer reagent of 2.5.For topical, the common amount of formula I is 0.001 to 20% of composition weight, such as 0.01% to about 10%.In embodiments of the invention, the amount of active compound is 0.05-1%.In one embodiment of the invention, the amount of active compound is 0.01-0.5%.In one embodiment of the invention, the concentration that exists of active compound is about 0.1%.In one embodiment of the invention, said composition comprises 0.005-0.1% active compound, 20-40% Virahol, 0.5-10% benzylalcohol, 0.5-5% Natvosol and citrate buffer to 100%.
Preparation for the ingenol derivative of the gel form of topical has been described in WO07/068963, is introduced into as a reference at this.
Preparation method
Formula I can such as utilize the variant of the known method of following summarized reaction and technology and synthetic organic chemistry field or method understood by one of ordinary skill in the art to prepare.Preferred method includes but not limited to those of the following stated.React and be suitable for reagent used and raw material and be suitable for carrying out in the solvent of carried out conversion.In addition, be to be understood that, in the synthetic method of the following stated, all proposed reaction conditionss, comprise the condition that solvent, reaction atmosphere, temperature of reaction, the time length of experiment and the selection of post-treating method all should be chosen to the standard of this reaction, this should be that those skilled in the art easily confirm.The not all compound falling into given classification some reaction conditionss all with required in described certain methods are mutually compatible.Apparent to those skilled in the art for the substituent restriction compatible with reaction conditions, and can alternative method be used.If necessary, by the standard method purifying that the compounds of this invention or any intermediate utilize synthesis of organic scholar known, such as W.Armarego " purifying of laboratory chemicals ", Butterworth-Heinemann, the 6th edition, the method described in 2009.Raw material is known compound, can buy, or prepares by conventional synthesis process well known by persons skilled in the art.
The compounds of this invention can such as be prepared according to non-limiting general method below and embodiment.
Scheme I
Scheme 2
Scheme 3
Scheme 4
Compound of Formula I can such as be synthesized according to scheme 1,2,3 or 4: according to such as " protecting group in organic synthesis ", the 4th edition .P.G.M.Wuts; T.W.Greene; JohnWiley; 2007 or P.J.Kocienski; " protecting group "; 3rd edition .G.Thieme; 2003 and the method described in wherein quoted reference, protect reagent react to obtain ingenol derivative a or c protected ingenol and hydroxy protecting agent or dihydroxyl.
Such as; compound a (wherein protecting group (Pg) is trityl group) can by by ingenol and trityl group reagent such as trityl group pyridine fluoroborate or trityl group chlorine at suitable solvent such as pyridine, N; react under the condition of presence or absence alkali in dinethylformamide or methylene dichloride and synthesize (the people such as such as Opferkuch; Z.Naturforschung; (1981); 36B, 878).
Compound a (wherein protecting group (Pg) is silyl) can such as pass through ingenol and silyl chloride such as tert-butyldimethylsilyl chloride, t-butyldiphenylsilyl chlorine or triisopropyl silyl chloride are at suitable solvent such as N, dinethylformamide, pyridine, methylene dichloride, at suitable alkali such as imidazoles in tetrahydrofuran (THF) or acetonitrile, triethylamine, N, N-diisopropyl ethyl amine or 4-(N, N-dimethylamino) pyridine existence under reaction synthesize (such as Sorg, B. etc., Z.Naturforsch., (1982), 37B, 1640-47), or by compound (II) and silyl triflate such as t-butyldimethylsilyl triflate are reacted to synthesize in suitable solvent such as methylene dichloride under the existence of suitable alkali such as triethylamine.
Compound a (wherein Pg is 2-THP trtrahydropyranyl) can such as by reacting to synthesize by ingenol and dihydropyrane in suitable solvent such as methylene dichloride or acetonitrile under the existence of suitable acid such as tosic acid.
Compound c (wherein protecting group (Pg) represents acetal such as benzylidene acetal) can such as by reacting to prepare by ingenol and phenyl aldehyde or benzaldehyde dimethyl acetal in suitable solvent such as methylene dichloride or DMF under the existence of suitable acid such as tosic acid.
Compound c (wherein protecting group (Pg) represents ketal such as isopropylidene ketal) can such as pass through ingenol and ketone such as acetone or dimethoxy ketal such as 2; 2-Propanal dimethyl acetal is at suitable solvent such as methylene dichloride or N; in dinethylformamide, under the existence of suitable acid such as tosic acid, reaction is synthesized (such as; B.Sorg; Z.Naturforsch. (1982); 37b, 748-756).Acetone and 2,2-dimethoxypropane also can serve as solvent.
As described in scheme 1 and 2, by protection ingenol derivative a or c according to such as " esterification ", J.Otera, Wiley-VCH, 2003 and the hydroxy esterification method esterification described in wherein quoted reference obtain general formula b or d compound.Compound b or d can such as by synthesizing the acid derivative of compound a or c and activation such as carboxylic acid halides such as acyl chloride reaction.By carrying out under the condition not having activator in suitable solvent such as methylene dichloride or toluene with the esterification of acyl chloride reaction, or can at alkali such as pyridine, triethylamine or 4-(N, N-dimethylamino) pyridine existence under carry out (such as, B.Sorg, Z.Naturforsch. (1982), 37b, 748-756).
Compound b or d can such as by synthesizing the acid derivative of compound a or c and activation such as anhydride reaction.By carrying out (such as under the condition not having catalyzer with the esterification of anhydride reaction, the people such as Opferkuch, Z.Naturforschung, (1981), 36B, 878), or under the existence of an acidic catalyst, utilize acid such as perchloric acid or Lewis acid such as trifluoromethanesulfonic acid scandium (III) or Bismuth triflate (III) to carry out, or carry out under the existence of alkali such as sodium bicarbonate or triethylamine.
Compound b or d can such as by synthesizing the mixed anhydride reaction of the acid derivative of compound a or c and activation such as acid such as trichlorobenzoic acid.By carrying out under the condition not having catalyzer in suitable solvent with the esterification of mixed anhydride reaction, or under the existence of an acidic catalyst, utilize acid such as perchloric acid or Lewis acid such as trifluoromethanesulfonic acid scandium (III) or Bismuth triflate (III) to carry out, or carry out under the existence of alkali such as sodium bicarbonate or triethylamine.
Compound b or d can such as by by compound a or c with sour at coupling agent as under the existence of carbodiimide such as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide, at presence or absence alkali such as 4-(N, N-dimethylamino) pyridine condition under utilize or do not utilize catalyzer such as 4-(N, N-dimethylamino) pyridine reacts and synthesizes (such as in suitable solvent such as methylene dichloride, Appendino etc., Eur.J.Org.Chem. (1999), 3413).The coupling agent of solid supported also can be used for esterif iotacation step [Nam, N.-H., JournalofCombinatorialChemistry, (2003), 5,479-545, or " esterification ", J.Otera, Wiley-VCH, 2003].
The formula b of above scheme 1 or 2, the compound of d or I can such as by lipase-catalyzed esterification by compound a, c or ingenol and acry radical donor such as acid anhydrides, ester such as vinyl ester or thioesters are reacted to synthesize under the existence of enzyme such as lipase or esterase.
As described in scheme 3 and 4; can according to such as " containing the functional group of carbonyl with at least one chalcogen (but not being halogen) "; H.Eckert; " ComprehensiveOrganicFunctionalGroupTransformationsII "; A.R.Katritzky and R.J.K.Taylor compiles; Vol6; p.440-444; Elsevier, 2005 and the formamyl method of the hydroxyl described in wherein quoted reference by the ingenol derivative a of protection or c formamyl to obtain the compound of general formula b or d.Compound b or d can such as by reacting to synthesize by the carbamic acid derivative of compound a or c and activation such as carbamyl halogen such as urea chloride.Can be carried out under the condition not having activator in suitable solvent such as acetonitrile, methylene dichloride or toluene by the formamylization of reacting with urea chloride; or can carry out under the existence of alkali such as pyridine, triethylamine, salt of wormwood or 4-(N, N-dimethylamino) pyridine.
Compound b or d can such as by synthesizing compound a or c and isocyanate reaction, with obtain N-mono--carbamate that replaces.Formed can carry out under the condition not having catalyzer in suitable solvent such as methylene dichloride or acetonitrile by the carbamate carried out with isocyanate reaction, or can carry out under the existence of alkali such as triethylamine.
Formula I, by preparing from the compound selective of general structure b or d removing protecting group Pg, is reacted according to such as but not limited to " protecting group in organic synthesis ", the 4th edition .P.G.M.Wuts; T.W.Greene, JohnWiley, 2007 or P.J.Kocienski, " protecting group ", the 3rd edition, G.Thieme, 2003 and the method for the eliminating hydroxide described in wherein quoted reference or dihydroxyl protecting group carry out.
Compound of Formula I can such as from general formula d compound (wherein Pg represents acetal such as benzylidene acetal or ketal such as isopropylidene ketal) by removing protecting group to prepare under the existence of suitable acid such as hydrochloric acid, acetic acid, trifluoroacetic acid or tosic acid in suitable solvent such as methyl alcohol or water-containing tetrahydrofuran.
Compound of Formula I can such as be passed through removing acetal moieties from general formula b compound (wherein Pg representation alkoxy alkyl such as 2-THP trtrahydropyranyl), such as be prepared in suitable solvent such as methyl alcohol under the existence of suitable acid such as tosic acid by acid-catalyzed cleavage.
Compound of Formula I can such as from general formula b compound (wherein Pg represents silyl such as t-butyldimethylsilyl) by compound b and suitable acid such as hydrochloric acid to be reacted suitable solvent such as methyl alcohol or by reacting to prepare in suitable solvent such as tetrahydrofuran (THF) or acetonitrile with the n-butyl Neutral ammonium fluoride in fluorine source such as four or tetrafluorosilane.
Compound of Formula I can such as from general formula b compound (wherein Pg represents trityl group) by compound b and suitable acid such as formic acid or trifluoroacetic acid are reacted to prepare suitable solvent such as ether, methyl alcohol or methylene dichloride.
Embodiment
general introduction
All raw materials used all can buy, unless otherwise described.For 1H nucleus magnetic resonance (NMR) spectrum, give chemical displacement value (δ) (ppm); Using tetramethylsilane (δ=0.00) as standard.Give the value of defined unimodal (s), bimodal (d), triplet (t), quartet (q) or scope (m).Carbamate may demonstrate the signal of repetition because there is cis/trans rotational isomer.All organic solvents used are all anhydrous, unless otherwise.Flash chromatography carries out on silica gel.Use the suitable mixture of ethyl acetate and heptane as eluent, except as otherwise noted.By compound on the tlc plate by detecting with potassium permanganate solution colour developing.
ingenol-5,20-contracting acetone
Ingenol (1.00g, 2.30mmol) is dissolved in the acetone soln (0.47mg/mL, 22.5mL) of tosic acid monohydrate.Solution is at room temperature stirred 25min.Saturated NaHCO is added in this solution 3the aqueous solution (0.2mL).By the mixture vacuum concentration obtained.In resistates, add salt solution and be extracted with ethyl acetate.The dry also vacuum concentration of ground organic phase with sodium sulfate will be merged.Resistates is obtained white solid title compound (616mg, 69%) by purification by flash chromatography (heptane/ethyl acetate 19:1 → heptane/ethyl acetate 0:1).(also can see: the people such as Opferkuch, H.J., Z.Naturforsch., (1981), 86b, 878-887.)
1HNMR(300MHz,CDCl 3)δ5.91(q,J=1.5Hz,1H),5.79(m,1H),4.25(d,J=4.5Hz,1H),4.20–4.07(m,3H),3.93(s,1H),3.51(s,1H),2.57–2.41(m,2H),2.25(ddd,J=15.7,8.4,2.9Hz,1H),1.85(d,J=1.5Hz,3H),1.77(dt,J=15.8,5.9Hz,1H),1.41(s,3H),1.35(s,3H),1.13(s,3H),1.05(s,3H),1.00–0.87(m,4H),0.70(td,J=8.4,6.4Hz,1H)。
prepare the general method of Compounds of formula II
method a
By formic acid (0.100mmol), dicyclohexylcarbodiimide (0.100mmol), 4-(N, N-dimethylamino) mixture of-pyridine (0.0025mmol) and ingenol-5,20-contracting acetone (0.050mmol) at room temperature stirs 20-24h in methylene dichloride.Mixture is mixed with ethyl acetate, filters and wash with saturated sodium-chloride water solution.Organic phase with sodium sulfate is dry, and vacuum concentration also obtains white solid title compound by purification by flash chromatography (heptane → heptane/ethyl acetate 7:3).
method b
By acyl chlorides (0.0625mmol), diisopropyl ethyl amine (0.075mmol), 4-(N, N-dimethylamino) mixture of-pyridine (0.070mmol) and ingenol-5,20-contracting acetone (0.050mmol) stirs 6-20h at 55 DEG C in tetrahydrofuran (THF).Mixture is mixed with ethyl acetate, filters and wash with saturated sodium-chloride water solution.Organic phase with sodium sulfate is dry, and vacuum concentration also obtains white solid title compound by purification by flash chromatography (heptane → heptane/ethyl acetate 7:3).
method c
By formic acid (0.100mmol), dicyclohexylcarbodiimide (0.100mmol), 4-(N, N-dimethylamino) mixture of-pyridine (0.025mmol) and ingenol-5,20-contracting acetone (0.050mmol) stirs 5min in microwave oven at 150 DEG C in acetonitrile.Mixture is mixed with ethyl acetate, filters and wash with saturated sodium-chloride water solution.Organic phase with sodium sulfate is dry, and vacuum concentration also obtains white solid title compound by purification by flash chromatography (heptane → heptane/ethyl acetate 7:3).
method d
By acyl chlorides (0.125mmol), diisopropyl ethyl amine (0.250mmol), 4-(N, N-dimethylamino) mixture of-pyridine (0.025mmol) and ingenol-5,20-contracting acetone (0.050mmol) stirs 10-30min in microwave oven at 150 DEG C in acetonitrile.Mixture is mixed with ethyl acetate, filters and wash with saturated sodium-chloride water solution.Organic phase with sodium sulfate is dry, and vacuum concentration also obtains white solid title compound by purification by flash chromatography (heptane → heptane/ethyl acetate 7:3).
the general method of preparation compound of Formula I
method e
Ingenol-5,20-contracting acetone-3-acylate or ingenol-5,20-contracting acetone-3-carbamate (0.10mmol) are dissolved in tetrahydrofuran (THF) (0.47mL) under argon gas.Add the HCl aqueous solution (4M, 4.7 μ L).Solution is at room temperature stirred 20-27h.Tetrahydrofuran (THF) methyl alcohol can be replaced and the reaction times is at room temperature foreshortened to 0.5h.By solution for vacuum concentration.Resistates is obtained title compound by purification by flash chromatography (heptane/ethyl acetate 5:1 → heptane/ethyl acetate 3:7).For the compound that polarity is stronger, methylene chloride/methanol 98:2 → methylene chloride/methanol 95:5 gradient can be utilized.
prepare the general method of urea chloride
method f
In methylene dichloride (2ml) solution of secondary amine (1.2mmol), at 0 DEG C, add saleratus (3.0mmol) or tertiary amine such as triethylamine or pyridine, then add triphosgene (1.0mmol).Mixture is stirred 2h at 0 DEG C, filters and use washed with dichloromethane.Title compound is obtained by concentrated for the filter vacuum of merging.
the general method of ingenol-5, the 20-contracting acetone-3-carbamate compounds of preparation general formula III
method g
The mixture of urea chloride (0.390mmol), salt of wormwood (0.616mmol) and ingenol-5,20-contracting acetone (0.077mmol) is stirred 16-24h at 80 DEG C in acetonitrile.Mixture is filtered and uses washed with dichloromethane.The filter vacuum merged is concentrated and passes through purification by flash chromatography (heptane → heptane/ethyl acetate 7:3) and obtains title compound.
method h
The mixture of urea chloride (0.390mmol), salt of wormwood (0.616mmol) and ingenol-5,20-contracting acetone (0.077mmol) is stirred 10min in microwave oven at 160 DEG C in acetonitrile.Mixture is filtered and uses washed with dichloromethane.The filter vacuum merged is concentrated and passes through purification by flash chromatography (heptane → heptane/ethyl acetate 7:3) and obtains title compound.
method i
The mixture of isocyanic ester (0.231mmol), salt of wormwood (0.385mmol) and ingenol-5,20-contracting acetone (0.077mmol) is stirred 16-24h at 80 DEG C in acetonitrile.Mixture is filtered and uses washed with dichloromethane.The filter vacuum merged is concentrated and passes through purification by flash chromatography (heptane → heptane/ethyl acetate 7:3) and obtains title compound.
method j
At 0 DEG C, THF (0.10mmol) solution of 1M (trimethyl silyl) lithamide is dripped under an argon in the tetrahydrofuran solution of ingenol-5,20-contracting acetone (0.10mmol).Stir dropping after 10 minutes be dissolved in the urea chloride (0.20mmol) of 0.2mlTHF and reaction mixture is slowly turned back to ambient temperature overnight.Mixture is added 2 drip, then add methylene dichloride (1ml), filter and vacuum concentration.Crude product is obtained title compound by purification by flash chromatography (heptane → heptane/ethyl acetate 7:3).
the general method of the 1-methylpyrazole-5-formic acid that preparation 4-aryl replaces
method k
Adopt the Angew.Chem.2006 such as G.C.Fu, the method described in 118,1304-1306.
The multiphase mixture of 1-methyl-4-bromine pyrazoles-5-formic acid (1mmol), three (dibenzalacetone) two palladium (0) (0.1mmol), tricyclohexyl phosphine (0.2mmol), potassiumphosphate (3mmol) and suitable phenyl-boron dihydroxide (1.5mmol), water (2mL) and dioxan (4mL) is stirred 20min under an argon in microwave oven at 180 DEG C.Mixture is cooled to room temperature and part evaporation, adds the 5NNaOH aqueous solution (1mL), with diethyl ether 3 times.The aqueous solution is used 4NHCl acidifying, by throw out by the filtering separation also dry 1-methylpyrazole-5-formic acid obtaining crude product 4-aryl and replace, it can use without being further purified.
preparation example 601:
ingenol-5,20-contracting acetone-3-(5-methyl-3-(the fluoro-phenyl of the chloro-6-of 2-)-different azoles-4-manthanoate (compound 601)
Compound 601 is prepared according to method d.
Raw material: 5-methyl-3-(the fluoro-phenyl of the chloro-6-of 2-)-different azoles-4-carbonyl chloride.
1HNMR(300MHz,CDCl 3)δ7.41-7.33(m,1H),7.27-7.24(m,1H),7.08-7.02(m,1H),5.85-5.84(d,1H),5.76-5.74(m,1H),5.57(s,1H),4.23-4.06(m,3H),3.94(s,1H),3.18(s,1H),2.82(s,3H),2.21-2.12(m,1H),1.96-1.90(m,1H),1.69-1.62(m,1H),1.61(d,3H),1.47(s,3H),1.39(s,3H),1.03(s,3H),1.03(s,3H),0.90-0.78(m,1H),0.73(d,3H),0.66-0.58(m,1H)。
preparation example 602:
ingenol-5,20-contracting acetone-3-(5-methyl-3-phenyl-different azoles-4-manthanoate) (compound 602)
Compound 602 is prepared according to method d.
Raw material: 5-methyl-3-phenyl-different azoles-4-carbonyl chloride.
1HNMR(300MHz,CDCl 3)δ7.57-7.53(m,2H),7.47-7.37(m,3H),5.95(d,1H),5.76(m,1H),5.68(s,1H),4.23-4.04(m,3H),3.97(s,1H),3.12(s,1H),2.77(s,3H),2.11-2.01(m,1H),1.95-1.87(m,1H),1.72(d,3H),1.59-1.49(m,1H),1.45(s,3H),1.40(s,3H),1.04(s,3H),1.03(s,3H),0.90-0.80(m,1H),0.71(d,3H),0.65-0.57(m,1H)。
preparation example 603
ingenol-5,20-contracting acetone-3-(1S-camphane acid esters) (compound 603)
Compound 603 is prepared according to method d.
Raw material: (1S)-Ci acyl chlorides.
1HNMR(300MHz,CDCl 3)δ6.10-6.09(m,1H),5.80-5.79(m,1H),5.66(s,1H),4.25-4.11(m,3H),4.02(s,1H),3.17(s,1H),2.61-2.56(m,1H),2.48-2.39(m,1H),2.29-2.20(m,1H),2.09-2.02(m,1H),1.94-1.88(m,1H),1.79-1.65(m,5H),1.45(s,3H),1.42(s,3H),1.12(s,3H),1.10(s,3H),1.09(s,3H),1.05(s,3H),0.99-0.86(m,7H),0.73-0.65(m,1H)。
preparation example 604:
ingenol-5,20-contracting acetone-3-(3-Phenyltriazole-4-manthanoate) (compound 604)
Compound 604 is prepared according to method c.
Raw material: 3-Phenyltriazole-4-formic acid.
preparation example 605:
ingenol-5,20-contracting acetone-3-(2-phenylpyrazole-3-manthanoate) (compound 605)
" urea chloride ", according to method h preparation, wherein replaces with 2-phenylpyrazole-3-carbonyl chloride by compound 605.
preparation example 606:
ingenol-5,20-contracting acetone-3-(1-methyl-benzdiazole-3-formic acid ester) (compound 606)
" urea chloride ", according to method h preparation, wherein replaces with 1-methylindazole-3-carbonyl chloride by compound 606.
preparation example 607:
ingenol-5,20-contracting acetone-3-(3-ethyl-5-methyl-different azoles-4-manthanoate) (compound 607)
Compound 607 is prepared according to method c.
Raw material: 3-ethyl-5-methyl-different azoles-4-formic acid.
1HNMR(300MHz,CDCl 3)6.12(m,1H),5.82-5.80(m,1H),5.72(s,1H),4.28-4.11(m,3H),4.05(s,1H),3.26(s,1H),2.89(q,2H),2.65(s,3H),2.63-2.59(m,1H),2.30-2.24(m,1H),1.81(d,3H),1.79-1.71(m,1H),1.48(s,3H),1.45(s,3H),1.28(t,3H),1.08(s,3H),1.05(s,3H),1.01(d,3H),0.94-0.86(m,1H),0.74-0.66(m,1H)。
preparation example 608:
ingenol-5,20-contracting acetone-3-(3,5-dimethyl-different azoles-4-manthanoate) (compound 608)
Compound 608 is prepared according to method c.
Raw material: 3,5-dimethyl-different azoles-4-formic acid.
1HNMR(300MHz,CDCl 3)6.12(s,1H),5.81-5.80(m,1H),5.70(s,1H),4.27-4.11(m,3H),4.05(s,1H),3.27(s,1H),2.65(s,3H),2.63-2.59(m,1H),2.43(s,3H),2.33-2.23(m,1H),1.82-1.70(m,4H),1.49(s,3H),1.45(s,3H),1.09(s,3H),1.05(s,3H),1.01(d,3H),0.94-0.87(m,1H),0.74-0.65(m,1H)。
preparation example 609:
ingenol-5,20-contracting acetone-3-(1-skatole-3-manthanoate) (compound 609)
Compound 609 is prepared according to method c.
Raw material: 1-skatole-3-formic acid.
preparation example 610:
ingenol-5,20-contracting acetone-3-(3-tolylthiophene-2-manthanoate) (compound 610)
Compound 610 is prepared according to method c.
Raw material: 3-tolylthiophene-2-formic acid.
preparation example 611:
(5-phenyl is different for ingenol-5,20-contracting acetone-3- azoles-3-manthanoate) (compound 611)
Compound 611 is prepared according to method d.
Raw material: 5-phenyl is different azoles-3-carbonyl chloride.
1HNMR(300MHz,CDCl 3)7.83-7.78(m,2H),7.52-7.47(m,3H),6.90(s,1H),6-16-6.15(m,1H),5.81(m,2H),4.28-4.08(m,4H),3.29(s,1H),2.73-2.68(m,1H),2.30-2.21(m,1H),1.85(d,3H),1.82-1.75(m,1H),1.50(s,3H),1.47(s,3H),1.08(s,3H),1.05(d,3H),1.04(s,3H),0.95-0.88(m,1H),0.74-0.67(m,1H)。
preparation example 612:
ingenol-5,20-contracting acetone-3-(isoquinoline 99.9-1-manthanoate) (compound 612)
Compound 612 is prepared according to method c.
Raw material: isoquinoline 99.9-1-formic acid.
1HNMR(300MHz,CDCl 3)δ8.76-8.73(m,1H),8.58(d,1H),7.90(d,1H),7.81(d,1H),7.77-7.72(m,1H),7.70-7.64(m,1H),6.15(m,1H),6.00(s,1H),5.82-5.80(m,1H),4.47(s,1H),4.29-4.22(m,3H),4.10(s,1H),2.74-2.69(m,1H),2.45-2.35(m,1H),1.90(d,3H),1.87-1.80(m,1H),1.49(s,3H),1.47(s,3H),1.15(s,3H),1.07(s,3H),0.98-0.88(m,4H),0.77-0.69(m,1H)。
preparation example 613:
ingenol-5,20-contracting acetone-3-(quinoline-4-manthanoate) (compound 613)
Compound 613 is prepared according to method c.
Raw material: quinoline-4-formic acid.
preparation example 614:
ingenol-5,20-contracting acetone-3-(cinnolines-4-manthanoate) (compound 614)
Compound 614 is prepared according to method c.
Raw material: cinnolines-4-formic acid.
1HNMR(300MHz,CDCl 3)δ9.71(s,1H),8.94-8.91(m,1H),8.67-8.64(m,1H),7.96-7.86(m,2H),6.21-6.20(m,1H),5.93(s,1H),5.85-5.84(m,1H),4.32-4.13(m,4H),3.36(s,1H),2.74-2.69(m,1H),2.38-2.28(m,1H),1.87(d,3H),1.86-1.79(m,1H),1.53(s,3H),1.52(s,3H),1.09(s,3H),1.05(s,3H),1.04(d,3H),0.96-0.89(m,1H),0.77-0.69(m,1H)。
preparation example 615:
ingenol-5,20-contracting acetone-3-(3-phenylimidazole-4-manthanoate) (compound 615)
Compound 615 is prepared according to method c.
Raw material: 3-phenylimidazole-4-formic acid.
1HNMR(300MHz,CDCl 3)δ7.89(d,1H),7.67(d,1H),7.48-7.45(m,3H),7.35-7.32(m,2H),6.00-5.99(m,1H),5.77-5.76(m,1H),5.62(s,1H),4.22-4.07(m,3H),3.97(bs,1H),3.17(s,1H),2.34-2.29(m,1H),2.25-2.16(m,1H),1.76-1.67(m,4H),1.40(s,3H),1.37(s,3H),1.07(s,3H),1.04(s,3H),0.92-0.84(m,4H),0.71-0.63(m,1H)。
preparation example 616:
ingenol-5,20-contracting acetone-3-(5-phenyl azoles-4-manthanoate) (compound 616)
Compound 616 is prepared according to method c.
Raw material: 5-phenyl azoles-4-formic acid.
1HNMR(300MHz,CDCl 3)δ7.95-7.91(m,3H),7.48-7.42(m,3H),6.07-6.06(m,1H),5.78-5.75(m,2H),4.24-4.08(m,3H),4.03-4.02(m,1H),3.39(s,1H),2.37-2.29(m,1H),2.20-2.11(m,1H),1.83(d,3H),1.68-1.58(m,1H),1.47(s,3H),1.43(s,3H),1.05(s,3H),1.03(s,3H),0.91-0.84(m,1H)0.84(d,3H),0.68-0.60(m,1H)。
preparation example 617:
ingenol-5,20-contracting acetone-3-(1,2-benzo azoles-3-manthanoate) (compound 617)
Compound 617 is prepared according to method c.
Raw material: 1,2-benzo azoles-3-formic acid.
1HNMR(300MHz,CDCl 3)δ8.14-8.11(m,1H),7.70-7.60(m,2H),7.46-7.39(m,1H),6.21-6.19(m,1H),5.89(s,1H),5.83-5.81(m,1H),4.30-4.11(m,4H),3.34(s,1H),2.77-2.72(m,1H),2.30-2.21(m,1H),1.89(d,3H),1.81-1.72(m,1H),1.52(s,3H),1.49(s,3H),1.07(s,3H),1.05(d,3H),1.04(s,3H),0.95-0.88(m,1H),0.74-0.66(m,1H)。
preparation example 618:
ingenol-5,20-contracting acetone-3-(3-sec.-propyl-5-methyl-different azoles-4-manthanoate) (compound 618)
Compound 618 is prepared according to method c.
Raw material: 3-sec.-propyl-5-methyl-different azoles-4-formic acid.
1HNMR(300MHz,CDCl 3)δ6.12-6.11(m,1H),5.82-5.79(m,1H),5.73(s,1H),4.28-4.10(m,3H),4.06-4.05(m,1H),3.46(septet,1H),3.26(s,1H),2.65(s,3H),2.63-2.57(m,1H),2.33-2.24(m,1H),1.81(d,3H),1.79-1.70(m,1H),1.48(s,3H),1.46(s,3H),1.33(d,3H),1.31(d,3H),1.08(s,3H),1.05(s,3H),1.00(d,3H),0.94-0.87(m,1H),0.74-0.66(m,1H)。
preparation example 619:
ingenol-5,20-contracting acetone-3-(3-(2-p-methoxy-phenyl)-5-methyl-different azoles-4-manthanoate) (compound 619)
Compound 619 is prepared according to method c.
Raw material: 3-(2-p-methoxy-phenyl)-5-methyl-different azoles-4-formic acid.
1HNMR(300MHz,CDCl 3)δ7.44-7.35(m,2H),7.04-6.99(m,1H),6.96-6.92(d,1H),5.93-5.91(m,1H),5.75-5.72(m,1H),5.67(s,1H),4.20-4.13(m,2H),4.06-4.00(m,1H),3.92(s,1H),3.76(s,3H),2.98(s,1H),2.74(s,3H),2.03-1.95(m,1H),1.87-1.78(m,1H),1.69(d,3H),1.58-1.50(m,1H),1.42(s,3H),1.38(s,3H),1.04(s,3H),1.03(s,3H),0.88-0.80(m,1H),0.76(d,3H),0.66-0.58(m,1H)。
preparation example 620:
ingenol-5,20-contracting acetone-3-(the bromo-2-methyl pyrazole of 4--3-manthanoate) (compound 620)
Compound 620 is prepared according to method c.
The bromo-2-methyl pyrazole of raw material: 4--3-formic acid.
preparation example 621:
ingenol-5,20-contracting acetone-3-(4-bromo-2-ethyl-pyrazoles-3-manthanoate) (compound 621)
Compound 621 is prepared according to method c.
Raw material: 4-bromo-2-ethyl-pyrazoles-3-formic acid.
preparation example 622:
ingenol-5,20-contracting acetone-3-(4-chloro-2-methyl-pyrazoles-3-manthanoate) (compound 622)
Compound 622 is prepared according to method c.
Raw material: 4-chloro-2-methyl-pyrazoles-3-formic acid.
preparation example 623:
ingenol-5,20-contracting acetone-3-(5-bromo pyrimi piperidine-4-manthanoate) (compound 623)
Compound 623 according to method d preparation, but will extend to 40min in the reaction times.
Raw material: 5-bromo pyrimi piperidine-4-carbonyl chloride, its from 5-bromo pyrimi piperidine-4-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ9.20(s,1H),9.00(s,1H),6.16-6.14(m,1H),5.85(s,1H),5.83-5.80(m,1H),4.27-4.14(m,3H),4.07-4.06(m,1H),3.44(s,1H),2.66-2.59(m,1H),2.31-2.22(m,1H),1.88(d,3H),1.79-1.70(m,1H),1.49(s,3H),1.46(s,3H),1.09(s,3H),1.05(s,3H),0.96(d,3H),0.95-0.88(m,1H),0.73-0.65(m,1H)。
preparation example 624:
ingenol-5,20-contracting acetone-3-(3-bromopyridine-2-manthanoate) (compound 624)
Compound 624 according to method d preparation, but will extend to 40min in the reaction times.
Raw material: 3-bromopyridine-2-carbonyl chloride, its from 3-bromopyridine-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ8.60(dd,1H),7.99(dd,1H),7.30(dd,1H),6.13-6.12(m,1H),5.89(s,1H),5.80-5.77(m,1H),4.20-4.15(m,3H),4.05(s,1H),3.85(s,1H),2.70-2.60(m,1H),2.32-2.23(m,1H),1.89(d,3H),1.80-1.71(m,1H),1.47(s,3H),1.44(s,3H),1.10(s,3H),1.05(s,3H),0.96(d,3H),0.95-0.89(m,1H),0.73-0.85(m,1H)。
preparation example 625:
ingenol-5,20-contracting acetone-3-(5-methylthiazol-4-manthanoate) (compound 625)
Compound 625 is prepared according to method c.
Raw material: 5-methylthiazol-4-formic acid.
1HNMR(300MHz,CDCl 3)δ8.85(s,1H),6.13-6.11(m,1H),5.79-5.77(m,2H),4.25-4.13(m,3H),4.06-4.05(m,1H),3.50(s,1H),2.78(s,3H),2.72-2.67(m,1H),2.31-2.22(m,1H),1.85(d,3H),1.81-1.72(m,1H),1.48(s,3H),1.45(s,3H),1.08(s,3H),1.05(s,3H),1.02(d,3H),0.95-0.88(m,1H),0.74-0.66(m,1H)。
preparation example 626:
ingenol-5,20-contracting acetone-3-(the chloro-1-methyl pyrazole of 4--3-manthanoate) (compound 626)
Compound 626 is prepared according to method c.
The chloro-1-methyl pyrazole of raw material: 4--3-formic acid.
preparation example 627:
ingenol-5,20-contracting acetone-3-(2,4-dimethylthiazole-5-manthanoate) (compound 627)
Compound 627 is prepared according to method c.
Raw material: 2,4-dimethylthiazole-5-formic acid.
1HNMR(300MHz,CDCl 3)δ6.10-6.09(m,1H),5.80-5.79(m,1H),5.68(s,1H),4.26-4.12(m,3H),4.04-4.03(m,1H),3.22(s,1H),2.70(s,3H),2.68(s,3H),2.68-2.63(m,1H),2.32-2.22(m,1H),1.82-1.73(m,4H),1.48(s,3H),1.44(s,3H),1.08(s,3H),1.05(s,3H),1.02(d,3H),0.94-0.88(m,1H),0.74-0.66(m,1H)。
preparation example 628:
ingenol-5,20-contracting acetone-3-(2,5-dimethyl azoles-4-manthanoate) (compound 628)
Compound 628 is prepared according to method c.
Raw material: 2,5-dimethyl azoles-4-formic acid.
1HNMR(300MHz,CDCl 3)δ6.10-6.09(m,1H),5.80-5.78(m,1H),5.73(s,1H),4.27-4.12(m,3H),4.04(bs,1H),3.37(s,1H),2.67-2.62(m,1H),2.55(s,3H),2.43(s,3H),2.31-2.22(m,1H),1.82(d,3H),1.79-1.71(m,1H),1.47(s,3H),1.41(s,3H),1.08(s,3H),1.04(s,3H),1.01(d,3H),0.94-0.87(m,1H),0.73-0.65(m,1H)。
preparation example 629:
ingenol-5,20-contracting acetone-3-(2,4-dimethyl furan-3-manthanoate) (compound 629)
Compound 629 is prepared according to method d.
Raw material: 2,4-dimethyl furan-3-carbonyl chloride.
1HNMR(300MHz,CDCl 3)δ7.05(q,1H),6.09-6.08(m,1H),6.80-6.78(m,1H),5.73(s,1H),4.26-4.12(m,3H),4.05(s,1H),3.34(s,1H),2.69-2.62(m,1H),2.54(s,3H),2.33-2.24(m,1H),2.13(d,3H),1.81(d,3H),1.78-1.69(m,1H),1.48(s,3H),1.44(s,3H),1.08(s,3H),1.05(s,3H),1.00(d,3H),0.91-0.86(m,1H),0.74-0.65(m,1H)。
preparation example 630:
(3,5-diethyl is different for ingenol-5,20-contracting acetone-3- azoles-4-manthanoate) (compound 630)
Compound 630 is prepared according to method d.
Raw material: 2,4-diethyl furans-3-carbonyl chloride, its from 2,4-diethyl furans-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.13-6.11(m,1H),5.82-5.80(m,1H),5.73(s,1H),4.28-4.11(m,3H),4.05(m,1H),3.26(s,1H),3.09(q,2H),2.89(q,2H),2.62-2.57(m,1H),2.34-2.24(m,1H),1.81(d,3H),1.79-1.70(m,1H),1.48(s,3H),1.45(s,3H),1.30(t,3H),1.29(t,3H),1.08(s,3H),1.05(s,3H),1.01(d,3H),0.93-0.87(m,1H),0.74-0.66(m,1H)。
preparation example 631:
ingenol-5,20-contracting acetone-3-(1H-indoles-7-manthanoate) (compound 631)
Compound 631 is prepared according to method c.
Raw material: 1H-indoles-7-formic acid.
preparation example 632:
ingenol-5,20-contracting acetone-3-(the 2-tertiary butyl-5-methyl pyrazole-3-manthanoate) (compound 632)
Compound 632 according to method c preparation, but replaces acetonitrile with DMF.
Raw material: the 2-tertiary butyl-5-methyl pyrazole-3-formic acid.
1HNMR(300MHz,CDCl 3)δ6.61(s,1H),6.08-6.06(m,1H),5.82-5.79(m,1H),5.70(s,1H),4.28-4.10(m,3H),4.05-4.04(m,1H),3.19(s,1H),2.67-2.61(m,1H),2.31-2.22(m,4H),1.83-1.74(m,4H),1.70(s,9H),1.47(s,3H),1.46(s,3H),1.10(s,3H),1.05(s,3H),1.01(d,3H),0.95-0.90(m,1H),0.74-0.67(m,1H)。
preparation example 633:
ingenol-5,20-contracting acetone-3-(the 5-tertiary butyl-2-methyl pyrazole-3-manthanoate) (compound 633)
Compound 633 according to method c preparation, but replaces acetonitrile with DMF.
Raw material: the 5-tertiary butyl-2-methyl pyrazole-3-formic acid.
preparation example 634:
ingenol-5,20-contracting acetone-3-(6-Methylimidazole is [2,1-b] thiazole-5-manthanoate also) (compound 634)
Compound 634 according to method c preparation, but replaces acetonitrile with DMF.
Raw material: 6-Methylimidazole is [2,1-b] thiazole-5-formic acid also.
preparation example 635:
ingenol-5,20-contracting acetone-3-(glyoxal ethyline is [1,2-a] Nicotinicum Acidum ester also) (compound635)
Compound 635 according to method c preparation, but replaces acetonitrile with DMF.
Raw material: glyoxal ethyline is [1,2-a] Nicotinicum Acidum also.
preparation example 636:
ingenol-5,20-contracting acetone-3-(2,4,5-trimethylammonium furans-3-manthanoate) (compound 636)
Compound 636 is prepared according to method c.
Raw material: 2,4,5-trimethylammonium furans-3-formic acid.
preparation example 637: ingenol-5,20-contracting acetone-3-(3 methyl thiophene-2-manthanoate) (compound 637)
Compound 637 is prepared according to method c.
Raw material: 3 methyl thiophene-2-formic acid.
preparation example 638:
ingenol-5,20-contracting acetone-3-(2-methyl-4-(piperidino) pyrazoles-3-manthanoate) (compound 638)
Compound 638 is prepared according to method d.
Raw material: 2-methyl-4-(piperidino) pyrazoles-3-carbonyl chloride, its from 2-methyl-4-(piperidino) pyrazoles-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ7.27(s,1H),6.15-6.13(m,1H),5.80-5.76(m,2H),4.26-4.4.10(m,6H),4.05-4.04(m,1H),3.58(s,1H),2.99-2.83(m,4H),2.77-2.72(m,1H),2.31-2.21(m,1H),1.84(d,3H),1.76-1.51(m,7H),1.49(s,3H),1.44(s,3H),1.07(s,3H),1.04(s,3H),1.01(d,3H),0.93-0.86(m,1H),0.72-0.64(m,1H)。
preparation example 639:
ingenol-5,20-contracting acetone-3-(the chloro-5-sec.-propyl-4-thiazolecarboxylic acid ester of 2-) (compound 639)
Compound 639 is prepared according to method c.
The chloro-5-sec.-propyl-4-thiazolecarboxylic acid of raw material: 2-.
1HNMR(300MHz,CDCl 3)δ6.13-6.12(m,1H),5.80-5.77(m,2H),4.25-4.03(m,5H),3.46(s,1H),2.70-2.65(m,1H),2.33-2.23(m,1H),1.83(d,3H),1.81-1.74(m,1H),1.47(s,3H),1.43(s,3H),1.32(d,6H),1.09(s,3H),1.05(s,3H),1.02(d,3H),0.95-0.88(m,1H),0.74-0.66(m,1H)。
preparation example 640:
ingenol-5,20-contracting acetone-3-(chloro-2, the 5-Dimethyl-pyrazol-3-manthanoate of 4-) (compound 640)
Compound 640 is prepared according to method c.
Chloro-2, the 5-Dimethyl-pyrazol-3-formic acid of raw material: 4-.
preparation example 641:
ingenol-5,20-contracting acetone-3-(1,2,4-trimethylammonium pyrroles-3-manthanoate) (compound 641)
Compound 641 is prepared according to method c.
Raw material: 1,2,4-trimethylammonium pyrroles-3-formic acid.
1HNMR(300MHz,CDCl 3)δ6.28(m,1H),6.06-6.04(m,1H),5.78-5.75(m,2H),4.21-4.15(m,3H),4.05-4.04(m,1H),3.52(s,1H),3.46(s,3H),2.73-2.68(m,1H),2.48(s,3H),2.33-2.23(m,1H),2.20(s,3H),1.81(d,3H),1.78-1.68(m,1H),1.48(s,3H),1.43(s,3H),1.07(s,3H),1.04(s,3H),0.99(d,3H),0.93-0.86(m,1H),0.72-0.64(m,1H)。
preparation example 642:
ingenol-5,20-contracting acetone-3-(1,3,5-trimethylammonium pyrroles-2-manthanoate) (compound 642)
Compound 642 is prepared according to method c.
Raw material: 1,3,5-trimethylammonium pyrroles-2-formic acid.
preparation example 643:
ingenol-5,20-contracting acetone-3-(1-ethyl-3,5-dimethyl pyrrole-2-manthanoate) (compound 643)
Compound 643 is prepared according to method c.
Raw material: 1-ethyl-3,5-dimethyl pyrrole-2-formic acid.
preparation example 644:
ingenol-5,20-contracting acetone-3-(1-t-butyloxycarbonyl-3,3-dimethyl pyrrolidine-2-formic acid ester) (compound 644)
Compound 644 is prepared according to method c.
Raw material: 1-t-butyloxycarbonyl-3,3-dimethyl pyrrolidine-2-formic acid.
preparation example 645:
ingenol-5,20-contracting acetone-3-((2S)-1-Phenylpyrrolidine-2-manthanoate) (compound 645)
Compound 645 according to method a preparation, but replaces methylene dichloride with acetonitrile and react 18h at 90 DEG C.
Raw material: (2S)-1-Phenylpyrrolidine-2-formic acid.
preparation example 646:
ingenol-5,20-contracting acetone-3-(1-sec.-propyl-3,5-Dimethyl-pyrazol-4-manthanoate) (compound 646)
Compound 646 is according to method d preparation, but temperature of reaction is 160 DEG C.
Raw material: 1-sec.-propyl-3,5-Dimethyl-pyrazol-4-carbonyl chloride, its from 1-sec.-propyl-3,5-Dimethyl-pyrazol-4-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.09-6.06(m,1H),5.80-5.77(m,1H),5.73(s,1H),4.42(septet,1H),4.25-4.12(m,3H),4.05(s,1H),3.39(s,1H),2.70-2.65(m,1H),2.52(s,3H),2.41(s,3H),2.33-2.24(m,1H),1.82(d,3H),1.78-1.69(m,1H),1.48-1.44(m,12H),1.07(s,3H),1.05(s,3H),1.00(d,3H),0.93-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 647:
ingenol-5,20-contracting acetone-3-(5-ethyl-3-sec.-propyl-different azoles-4-manthanoate) (compound 647)
Compound 647 according to method a preparation, but replaces methylene dichloride with acetonitrile and react 18h at 90 DEG C.
Raw material: 5-ethyl-3-sec.-propyl-different azoles-4-formic acid.
preparation example 648:
ingenol-5,20-contracting acetone-3-(2-methyl-benzdiazole-3-formic acid ester) (compound 648)
Compound 648 according to method a preparation, but replaces methylene dichloride with acetonitrile and react 18h at 90 DEG C.
Raw material: 2-methyl-benzdiazole-3-formic acid.
preparation example 649:
ingenol-5, the 20-contracting acetone-3-(5-methyl-3-tertiary butyl-different azoles-4-manthanoate) (compound 648)
Compound 649 is prepared according to method c.
Raw material: the 5-methyl-3-tertiary butyl-different azoles-4-formic acid.
preparation example 650:
ingenol-5,20-contracting acetone-3-(2-methyl-3-oxo-4-oxaspiro [4.5]-1-in last of the ten Heavenly stems alkene-1-formic acid ester) (compound 650)
Temperature of reaction according to method c preparation, but is kept 1h by compound 650 at 140 DEG C.
Raw material: 2-methyl-3-oxo-4-oxaspiro [4.5]-1-in last of the ten Heavenly stems alkene-1-formic acid.
preparation example 651:
ingenol-5,20-contracting acetone-3-(the 1-tertiary butyl-3,5-Dimethyl-pyrazol-4-manthanoate) (compound 651)
Compound 651 is prepared according to method c.
Raw material: the 1-tertiary butyl-3,5-Dimethyl-pyrazol-4-formic acid.
preparation example 652:
ingenol-5,20-contracting acetone-3-(3,5-dimethyl isothiazole-4-manthanoate) (compound 652)
Compound 652 is prepared according to method c.
Raw material: 3,5-dimethyl isothiazole-4-formic acid.
preparation example 653:
ingenol-5,20-contracting acetone-3-(the iodo-3-methyl-isothiazol of 5--4-manthanoate) (compound 653)
Compound 653 is prepared according to method c.
The iodo-3-methyl-isothiazol of raw material: 5--4-formic acid.
preparation example 654:
ingenol-5,20-contracting acetone-3-(4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-manthanoate) (changes compound 654)
Compound 654 is prepared according to method d.
Raw material: 4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-carbonyl chloride, its from 4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-formic acid is prepared as raw material according to method k (4-p-methoxy-phenyl) boric acid.
1HNMR(300MHz,CDCl 3)δ7.43(s,1H),7.28-7.23(m,2H),6.88-6.82(m,2H),5.95-5.94(m,1H),5.76-5.71(m,1H),5.71(s,1H),4.22(s,3H),4.20-4.00(m,3H),3.96(t,1H),3.81(s,3H),3.07(s,1H),2.04-1.94(m,1H),1.75-1.70(m,4H),1.52-1.45(m,4H),1.41(s,3H),1.02(s,6H),0.90-0.78(m,1H),0.68(d,3H),0.63-0.55(m,1H)。
preparation example 655:
ingenol-5,20-contracting acetone-3-(4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-manthanoate) (chemical combination thing 655)
Compound 655 is according to method d preparation, but temperature of reaction is 100 DEG C.
Raw material: 4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-carbonyl chloride, its from 4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-formic acid is prepared as raw material according to method k (2-aminomethyl phenyl) boric acid.
1HNMR(300MHz,CDCl 3)δ7.37(s,1H),7.22-7.09(m,4H),5.83-5.82(m,1H),5.74-5.72(m,1H),5.60(s,1H),4.25(s,3H),4.21-3.99(m,3H),3.91(s,1H),2.99(s,1H),2.14(s,3H),2.04-1.95(m,1H),1.72-1.67(m,1H),1.58-1.53(d,4H),1.47(s,3H),1.39(s,3H),1.03(s,6H),0.84-0.77(m,1H),0.69(d,3H),0.64-0.56(m,1H)。
preparation example 656:
ingenol-5,20-contracting acetone-3-(2-methyl-4-(4-methylsulfonyl phenyl) pyrazoles-3-manthanoate) (compound 656)
Compound 656 is according to method d preparation, but temperature of reaction is 100 DEG C.
Raw material: 4-(4-methylsulfonyl phenyl)-2-methyl pyrazole-3-carbonyl chloride, its from 4-(4-methylsulfonyl phenyl)-2-methyl pyrazole-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.4-(4-methylsulfonyl phenyl)-2-methyl pyrazole-3-formic acid is prepared as raw material according to method k (4-methylsulfonyl phenyl) boric acid.
1HNMR(300MHz,CDCl 3)δ7.97-7.89(m,2H),7.63-7.54(m,2H),7.51(s,1H),5.98-5.96(m,1H),5.78-5.75(m,1H),5.68(s,1H),4.25(s,3H),4.20-3.98(m,4H),3.18(s,1H),3.06(s,3H),2.12-2.03(m,1H),1.92-1.87(m,1H),1.69(d,3H),1.59-1.50(m,1H),1.48(s,3H),1.43(s,3H),1.03(s,3H),1.02(s,3H),0.86-0.79(m,1H),0.68(d,3H),0.65-0.57(m,1H)。
preparation example 657:
ingenol-5,20-contracting acetone-3-(2-methyl 4-phenyl-pyrazoles-3-manthanoate) (compound 657)
Compound 657 is according to method d preparation, but temperature of reaction is 100 DEG C.
Raw material: 2-methyl 4-phenyl-pyrazoles-3-carbonyl chloride, its from 2-methyl 4-phenyl-pyrazoles-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.2-methyl 4-phenyl-pyrazoles-3-formic acid is prepared as raw material according to method k phenyl-boron dihydroxide.
1HNMR(300MHz,CDCl 3)δ7.46(s,1H),7.34-7.28(m,5H),5.91(m,1H),5,75-5.73(m,1H),5.69(s,1H),4.23-3.94(m,7H),3.08(s,1H),2.03-1.93(m,1H),1.80-1.73(m,1H),1.67(d,3H),1.52-1.44(m,4H),1.41(s,3H),1.02(s,3H),1.02(s,3H),0.84-0.78(m,1H),0.65(d,3H),0.62-0.54(m,1H)。
preparation example 658:
ingenol-5,20-contracting acetone-3-(3,5-dimethyl-1-phenyl-pyrazole-4-manthanoate) (compound 658)
Compound 658 is according to method d preparation, but temperature of reaction is 140 DEG C.
Raw material: 3,5-dimethyl-1-phenyl-pyrazole-4-formic acid.
1HNMR(300MHz,CDCl 3)δ7.52-7.37(m,5H),6.11-6.10(m,1H),5.81-5.78(m,2H),4.27-4.12(m,3H),4.07(s,1H),3.41(s,1H),2.73-2.68(m,1H),2.53(s,3H),2.50(s,3H),2.36-2.26(m,1H),1.84(d,3H),1.80-1.71(m,1H),1.50(s,3H),1.46(s,3H),1.08(s,3H),1.05(s,3H),1.01(d,3H),0.94-0.87(m,1H),0.74-0.68(m,1H).
preparation example 659:
ingenol-5,20-contracting acetone-3-(1,5-dimethyl-3-phenyl-pyrazole-4-manthanoate) (compound 659)
Compound 659 is prepared according to method d.
Raw material: 1,5-dimethyl-3-phenyl-pyrazole-4-formic acid.
1HNMR(300MHz,CDCl 3)δ7.51-7.46(m,2H),7.38-7.31(m,3H),5.90-5.89(m,1H),5.74-5.71(m,2H),4.16-3.94(m,4H),3.84(s,3H),3.12(s,1H),2.60(s,3H),2.03-1.93(m,1H),1.85-1.80(m,1H),1.71(d,3H),1.52-1.46(m,4H),1.39(s,3H),1.02(s,3H),1.02(s,3H),0.85-0.79(m,1H),0.67(d,3H),0.63-0.55(m,1H)。
preparation example 660:
ingenol-5,20-contracting acetone-3-(1-benzyl-3,5-Dimethyl-pyrazol-4-manthanoate) (compound 660)
Compound 660 is prepared according to method d.
Raw material: 1-benzyl-3,5-Dimethyl-pyrazol-4-formic acid.
1HNMR(300MHz,CDCl 3)δ7.36-7.25(m,3H),7.14-7.11(m,2H),6.09-6.07(m,1H),5.80-5.77(m,1H),5.73(s,1H),5.24(s,2H),4.26-4.11(m,3H),4.05(s,1H),3.38(s,1H),2.69-2.64(m,1H),2.47(s,3H),2.44(s,3H),2.33-2.23(m,1H),1.81(d,3H),1.78-1.70(m,1H),1.47(s,3H),1.43(s,3H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.94-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 661:
ingenol-5,20-contracting acetone-3-(3,5-dimethyl-1-(tetrahydropyran-4-base methyl) pyrazoles-4-first acid esters) (compound 661)
Compound 661 by 120 DEG C in microwave oven by ingenol-5,20-contracting acetone-3-(3,5-dimethyl-1H-pyrazoles-4-manthanoate) prepared by (15mg), 4-iodomethyl-tetrahydrochysene-2H-pyrans (80mg) and salt of wormwood (40mg) the mixture heating 20min in DMF (0.5ml).Add water and use dichloromethane extraction, then evaporating solvent obtains crude product, and crude product is obtained title compound by chromatography according to the method purifying described in method c.Ingenol-5,20-contracting acetone-3-(3,5-dimethyl-1H-pyrazoles-4-manthanoate) is prepared as raw material by method c 3,5-dimethyl-1H-pyrazoles-4-formic acid.
preparation example 662:
ingenol-5,20-contracting acetone-3-(4-methyl-2-oxo-3H-thiazole-5-manthanoate) (compound 662)
Compound 662 is prepared according to method d.
Raw material: 4-methyl-2-oxo-3H-thiazole-5-carbonyl chloride, its from 4-methyl-2-oxo-3H-thiazole-5-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 663:
ingenol-5,20-contracting acetone-3-(2-methyl-4,5,6,7-tetrahydrochysene indazole-3-manthanoate) (compound 663)
Compound 663 is prepared according to method d.
Raw material: 2-methyl-4,5,6,7-tetrahydrochysene indazole-3-carbonyl chloride, it is from 2-methyl-4,5,6,7-tetrahydrochysene indazole-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.12-6.11(m,1H),5.81-5.79(m,1H),5.72(s,1H),4.28-4.06(m,7H),3.30(s,1H),2.72-2.61(m,5H),2.32-2.23(m,1H),1.82-1.66(m,8H),1.49(s,3H),1.45(s,3H),1.08(s,3H),1.05(s,3H),1.01(d,3H),0.93-0.87(m,1H),0.73-0.65(m,1H)。
preparation example 664:
ingenol-5,20-contracting acetone-3-(1,2-dimethyl indole-3-manthanoate) (compound 664)
Compound 664 is prepared according to method d.
Raw material: 1,2-dimethyl indole-3-carbonyl chloride, its from 1,2-dimethyl indole-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ8.12-8.09(m,1H),7.32-7.18(m,3H),6.14(m,1H),5.84(s,1H),5.79-5.77(m,1H),4.26-4.10(m,4H),3.70(s,3H),3.55(s,1H),2.84-2.77(m,4H),2.33-2.24(m,1H),1.88(d,3H),1.74-1.63(m,1H),1.51(s,3H),1.46(s,3H),1.06-1.03(m,9H),0.93-87(m,1H),0.72-0.64(m,1H)。
preparation example 665:
ingenol-5,20-contracting acetone-3-(5-methoxyl group-1,2-dimethyl-indol-3-manthanoate) (compound 665)
Compound 665 is prepared according to method d, but the reaction times extends to 75min.
Raw material: 5-methoxyl group-1,2-dimethyl-indol-3-carbonyl chloride, its from 5-methoxyl group-1,2-dimethyl-indol-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ7.64(d,1H),7.18(d,1H),6.87(dd,1H),6.14-6.12(m,1H),5.84(s,1H),5.80-5.77(m,1H),4.26-4.07(m,4H),3.84(s,3H),3.67(s,3H),3.63(s,1H),2.81-2.75(m,4H),2.32-2.22(m,1H),1.89(d,3H),1.74-1.65(m,1H),1.51(s,3H),1.46(s,3H),1.06(s,3H),1.03(s,3H),1.02(d,3H),0.97-0.87(m,1H),0.71-0.63(m,1H).
preparation example 666:
ingenol-5,20-contracting acetone-3-(1,3,5-trimethylpyrazol-4-manthanoate) (compound 666)
Compound 666 is prepared according to method d.
Raw material: 1,3,5-trimethylpyrazol-4-carbonyl chloride, its from 1,3,5-trimethylpyrazol-4-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.09-6.08(m,1H),5.80-5.77(m,1H),5.73(s,1H),4.26-4.05(m,4H),3.73(s,3H),3.39(s,1H),2.69-2.64(m,1H),2.49(s,3H),2.39(s,3H),2.33-2.23(m,1H),1.82(d,3H),1.77-1.68(m,1H),1.48(s,3H),1.44(s,3H),1.07(s,3H),1.05(s,3H),1.00(d,3H),0.93-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 667:
ingenol-5,20-contracting acetone-3-(4-methyl isophthalic acid, 2,5- diazole-3-manthanoate) (compound 667)
Compound 667 is prepared according to method d.
Raw material: 4-methyl isophthalic acid, 2,5 diazole-3-carbonyl chloride, it is from 4-methyl isophthalic acid, and 2,5 diazole-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 668:
ingenol-5,20-contracting acetone-3-(2-methoxyl group-4-methyl-thiazole-5-manthanoate) (compound 668)
Compound 668 is prepared according to method d.
Raw material: 2-methoxyl group-4-methyl-thiazole-5-carbonyl chloride, its from 2-methoxyl group-4-methyl-thiazole-5-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 669:
(4,5-dimethyl is different for ingenol-5,20-contracting acetone-3- azoles-3-manthanoate) (compound 669)
Compound 669 is prepared according to method d.
Raw material: 4,5-dimethyl is different azoles-3-carbonyl chloride, its from 2-methoxyl group-4-methyl-thiazole-5-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 670:
ingenol-5,20-contracting acetone-3-(the bromo-1-methyl pyrazole of 4--3-manthanoate) (compound 670)
Compound 670 is prepared according to method d.
The bromo-1-methyl pyrazole of raw material: 4--3-carbonyl chloride, its from the bromo-1-methyl pyrazole of 4--3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 671:
ingenol-5,20-contracting acetone-3-(1,3-dimethyl indole-2-manthanoate) (compound 671)
Compound 671 is prepared according to method d.
Raw material: 1,3-dimethyl indole-2-carbonyl chloride, its from 1,3-dimethyl indole-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 672:
ingenol-5,20-contracting acetone-3-(5-methoxyl group-1,3-dimethyl-indol-2-manthanoate) (compound 672)
Compound 672 is prepared according to method d.
Raw material: 5-methoxyl group-1,3-dimethyl-indol-2-carbonyl chloride, its from 5-methoxyl group-1,3-dimethyl-indol-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 673:
ingenol-5,20-contracting acetone-3-(2,4-dimethyl-6-oxo-pyrans-3-manthanoate) (compound 673)
Compound 673 is prepared according to method c.
Raw material: 2,4-dimethyl-6-oxo-pyrans-3-formic acid.
preparation example 674:
ingenol-5,20-contracting acetone-3-(1-methyl-3-phenyl-indole-2-manthanoate) (compound 674)
Compound 674 is prepared according to method d.
Raw material: 1-methyl-3-phenyl-indole-2-carbonyl chloride, its from 1-methyl-3-phenyl-indole-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 675:
(3-methyl-5-(trifluoromethyl) is different for ingenol-5,20-contracting acetone-3- azoles-4-manthanoate) (chemical combination thing 675)
Compound 675 is prepared according to method c.
Raw material: 3-methyl-5-(trifluoromethyl) is different azoles-4-formic acid.
preparation example 676:
ingenol-5,20-contracting acetone-3-(1,3-dimethyl pyrrole-2-manthanoate) (compound 676)
Reaction conditions according to method c preparation, but changes to react 60min at 140 DEG C by compound 676.
Raw material: 1,3-dimethyl pyrrole-2-formic acid.
preparation example 677:
ingenol-5,20-contracting acetone-3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl) pyrazoles-4-manthanoate) (compound 677)
Compound 677 is prepared according to method d.
Raw material: 3,5-dimethyl-1-(2,2,2-trifluoroethyl) pyrazoles-4-carbonyl chloride, it is from 2,2,2-trifluoroethyl) pyrazoles-4-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.11-6.09(m,1H),5.80-5.79(m,1H),5.73(s,1H),4.61(q,2H),4.27-4.05(m,4H),3.35(s,1H),2.68-2.61(m,1H),2.56(s,3H),2.41(s,3H),2.35-2.24(m,1H),1.82(d,3H),1.79-1.70(m,1H),1.48(s,3H),1.45(s,3H),1.08(s,3H),1.05(s,3H),1.01(d,3H),0.93-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 678:
ingenol-5,20-contracting acetone-3-(1-cyclopropyl-2,5-Dimethyl-pyrrol-3-manthanoate) (compound 678)
Compound 678 according to method d preparation, but will extend to 60min. in the reaction times
Raw material: 1-cyclopropyl-2,5-Dimethyl-pyrrol-3-carbonyl chloride, its from 1-cyclopropyl-2,5-Dimethyl-pyrrol-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.16(m,1H),6.04-6.02(m,1H),5.77-5.74(m,1H),5.73(s,1H),4.18-4.13(m,3H),4.03(s,1H),3.36(s,1H),2.94-2.86(m,1H),2.71-2.66(m,1H),2.59(s,3H),2.32-2.23(m,4H),1.80-1.71(m,4H),1.46(s,3H),1.42(s,3H),1.13-1.07(m,5H),1.04(s,3H),1.02(d,3H),0.94-0.88(m,3H),0.73-0.65(m,1H)。
preparation example 679:
ingenol-5,20-contracting acetone-3-(1,2,5-trimethylammonium pyrroles-3-manthanoate) (compound 679)
Compound 679 according to method d preparation, but will extend to 100min in the reaction times.
Raw material: 1,2,5-trimethylammonium pyrroles-3-carbonyl chloride, its from 1,2,5-trimethylammonium pyrroles-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.22-6.21(m,1H),6.04-6.02(m,1H),5.77-5.73(m,2H),4.19-4.14(m,3H),4.03(s,1H),3.40(s,3H),3.38(s,1H),2.72-2.66(m,1H),2.51(s,3H),2.32-2.23(m,1H),2.19(d,3H),1.80(d,3H),1.78-1.71(m,1H),1.47(s,3H),1.42(s,3H),1.07(s,3H),1.04(s,3H),1.02(d,3H),0.94-0.88(m,1H),0.73-0.65(m,1H)。
preparation example 680:
ingenol-5,20-contracting acetone-3-(2,4-dimethyl-1H-pyrroles-3-manthanoate) (compound 680)
Compound 680 is prepared according to method d.
Raw material: 2,4-dimethyl-1H-pyrroles-3-carbonyl chloride, its from 2,4-dimethyl-1H-pyrroles-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ10.40bs,1H),6.11-6.10(m,1H),5.96-5.95(m,1H),5.86-5.83(m,1H),5.75(s,1H),4.30-4.10(m,4H),3.72(bs,1H),2.66-2.61(m,1H),2.41(s,3H),2.33-2.23(m,4H),1.87-1.76(m,4H),1.47(s,3H),1.46(s,3H),1.12(s,3H),1.07(s,3H),0.97(d,3H),0.95-0.89(m,1H),0.77-0.69(m,1H)。
preparation example 681:
ingenol-5,20-contracting acetone-3-(1-methylpyrrole-2-manthanoate) (compound 681)
Compound 681 is prepared according to method d.
Raw material: 1-methylpyrrole-2-carbonyl chloride, its from 1-methylpyrrole-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 682:
ingenol-5,20-contracting acetone-3-(4-methyl isophthalic acid H-pyrroles-2-manthanoate) (compound 682)
Compound 682 according to method d preparation, but will extend to 75min in the reaction times.
Raw material: 4-methyl isophthalic acid H-pyrroles-2-carbonyl chloride, its from 4-methyl isophthalic acid H-pyrroles-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ8.97(bs,1H),6.76-6.72(m,2H),6.08-6.07(m,1H),5.79-5.76(m,1H),5.70(s,1H),4.25-4.12(m,3H),4.04-4.03(m,1H),3.29(s,1H),2.67-2.62(m,1H),2.31-2.21(m,1H),2.12(s,3H),1.82-1.73(m,4H),1.47(s,3H),1.43(s,3H),1.08(s,3H),1.04(s,3H),1.03(d,3H),0.95-0.88(m,1H),0.74-0.66(m,1H)。
preparation example 683:
ingenol-5,20-contracting acetone-3-(1,5-dimethyl pyrrole-2-manthanoate) (compound 683)
Compound 683 according to method c preparation, but will extend to 40min in the reaction times.
Raw material: 1,5-dimethyl pyrrole-2-formic acid.
preparation example 684:
ingenol-5,20-contracting acetone-3-(3-methyl isophthalic acid H-pyrroles-2-manthanoate) (compound 684)
Compound 684 according to method c preparation, but will extend to 40min in the reaction times.
Raw material: 3-methyl isophthalic acid H-pyrroles-2-formic acid.
1HNMR(300MHz,CDCl 3)δ8.93(bs,1H),6.86(t,1H),6.12-6.08(m,2H),5.80-5.77(m,1H),5.71(s,1H),4.26-4.13(m,3H),4.05-4.04(m,1H),3.38(s,1H),2.69-2.64(m,1H),2.35-2.23(m,4H),1.82(d,3H),1.79-1.70(m,1H),1.48(s,3H),1.44(s,3H),1.07(s,3H),1.04(s,3H),1.02(d,3H),0.94-0.88(m,1H),0.73-0.65(m,1H)。
preparation example 685:
ingenol-5,20-contracting acetone-3-(1-cyclopropyl pyrroles-2-manthanoate) (compound 685)
Compound 685 is prepared according to method d.
Raw material: 1-cyclopropyl pyrroles-2-carbonyl chloride, its from 1-cyclopropyl pyrroles-2-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.92(dd,1H),6.88(t,1H),6.09-6.06(m,2H),5.79-5.75(m,2H),4.24-4.13(m,3H),4.05-4.04(m,1H),3.79-3.71(m,1H),3.32(s,1H),2.70-2.65(m,1H),2.32-2.23(m,1H),1.84-1.73(m,4H),1.47(s,3H),1.44(s,3H),1.09(s,3H),1.05-0.88(m,11H),0.74-0.66(m,1H)。
preparation example 686:
ingenol-5,20-contracting acetone-3-(1-ethyl-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 686)
Compound 686 is prepared according to method d.
Raw material: 1-ethyl-2,4-Dimethyl-pyrrol-3-carbonyl chloride, its from 1-ethyl-2,4-Dimethyl-pyrrol-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.33-6.32(m,1H),6.06-6.04(m,1H),5.77-5.75(m,2H),4.21-4.17(m,3H),4.04(s,1H),3.81(t,2H),3.54(s,1H),2.74-2.69(m,1H),2.50(s,3H),2.34-2.24(m,1H),2.21(s,3H),1.82(d,3H),1.76-1.67(m,1H),1.47(s,3H),1.42(s,3H),1.33(t,3H),1.07(s,3H),1.04(s,3H),0.99(d,3H),0.93-0.86(m,1H),0.72-0.64(m,1H)。
preparation example 687:
ingenol-5,20-contracting acetone-3-(1-allyl group-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 687)
Compound 687 is prepared according to method d.
Raw material: 1-allyl group-2,4-Dimethyl-pyrrol-3-carbonyl chloride, its from 1-allyl group-2,4-Dimethyl-pyrrol-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 688:
ingenol-5,20-contracting acetone-3-(1-(Cvclopropvlmethvl)-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 688)
Compound 688 is prepared according to method d.
Raw material: 1-(Cvclopropvlmethvl)-2,4-Dimethyl-pyrrol-3-carbonyl chloride, its from 1-(Cvclopropvlmethvl)-2,4-Dimethyl-pyrrol-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
preparation example 689:
ingenol-5,20-contracting acetone-3-(1-(2-methoxy ethyl)-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 689)
Compound 689 is prepared according to method d.
Raw material: 1-(2-methoxy ethyl)-2,4-Dimethyl-pyrrol-3-carbonyl chloride, its from 1-(2-methoxy ethyl)-2,4-Dimethyl-pyrrol-3-formic acid by with 1.25 equivalents of oxalyl chloride at room temperature react in methylene dichloride and 1 dimethyl formamide 30 minutes, then vacuum-evaporation volatile matter prepare.
1HNMR(300MHz,CDCl 3)δ6.36(m,1H),6.06-6.04(m,1H),5.77-5.75(m,2H),4.21-4.14(m,3H),4.04(s,1H),3.94(t,2H),3.58(t,2H),3.53(s,1H),3.33(s,3H),2.73-2.68(m,1H),2.51(s,3H),2.33-2.23(m,1H),2.20(d,3H),1.81(d,3H),1.76-1.67(m,1H),1.47(s,3H),1.42(s,3H),1.07(s,3H),1.04(s,3H),0.99(d,3H),0.93-0.86(m,1H),0.72-0.64(m,1H)。
preparation example 801:
ingenol-5,20-contracting acetone-3-(N-Ethyl-carbamic acid ester) (compound 801)
Compound 801 is prepared according to method i.
Raw material: ethyl isocyanate.
preparation example 802:
ingenol-5,20-contracting acetone-3-(N, N-dimethyl-amino manthanoate) (compound 802)
Compound 802 is prepared according to method g.
Raw material: N, N-dimethylcarbamyl chloride.
preparation example 803:
ingenol-5,20-contracting acetone-3-(morpholine-4-manthanoate) (compound 803)
Compound 803 is prepared according to method g.
Raw material: morpholine-4-carbonyl chloride.
1HNMR(300MHz,CDCl 3)δ6.04-6.03(m,1H),5.77-5.76(m,1H),5.45(s,1H),4.23-4.12(m,3H),3.97(s,1H),3.70-3.63(m,4H),3.50-3.47(m,5H),2.52-2.47(m,1H),2.34-2.25(m,1H),1.78(d,3H),1.77-1.70(m,1H),1.46(s,3H),1.39(s,3H),1.10(s,3H),1.05(s,3H),0.97(d,3H),0.94-0.85(m,1H),0.73-0.65(m,1H)。
preparation example 804:
ingenol-5,20-contracting acetone-3-(tetramethyleneimine-1-manthanoate) (compound 804)
Compound 804 is prepared according to method g.
Raw material: tetramethyleneimine-1-carbonyl chloride.
1HNMR(300MHz,CDCl 3)δ6.01(m,1H),5.76-5.74(m,1H),5.44(s,1H),4.16-4.11(m,3H),3.96(s,1H),3.65(s,1H),3.44-3.33(m,4H),2.61-2.55(m,1H),2.33-2.44(m,1H),1.90-1.85(m,4H),1.79(d,3H),1.78-1.70(m,1H),1.45(s,3H),1.38(s,3H),1.10(s,3H),1.05(s,3H),0.98(d,3H),0.94-0.85(m,1H),0.72-0.65(m,1H)。
preparation example 805:
ingenol-5,20-contracting acetone-3-(N-Methyl-N-phenyl-carbamate) (compound 805)
Compound 805 is prepared according to method g.
Raw material: N-Methyl-N-phenyl-urea chloride.
preparation example 806:
ingenol-5,20-contracting acetone-3-(N, N-Diethyl-carbamic acid ester) (compound 806)
Compound 806 is prepared according to method g.
Raw material: N, N-diethyl-amino formyl chloride.
preparation example 807:
ingenol-5,20-contracting acetone-3-(piperidines-1-manthanoate) (compound 807)
Compound 807 is prepared according to method g.
Raw material: piperidines-1-carbonyl chloride.
preparation example 808:
ingenol-5,20-contracting acetone-3-(N-Benzyl-N-methyl-carbamate) (compound 808)
Compound 808 is prepared according to method g.
Raw material: N-Benzyl-N-methyl-urea chloride, it is prepared from N-Benzyl-N-methyl-amine according to method f.
preparation example 809:
ingenol-5,20-contracting acetone-3-(N-cyclohexyl-N-methyl-carbamate) (compound 809)
Compound 809 is prepared according to method g.
Raw material: N-cyclohexyl-N-methyl-urea chloride, it is prepared from N-cyclohexyl-N-methyl-amine according to method f.
preparation example 810:
ingenol-5,20-contracting acetone-3-(N-cyclohexyl-carbamate) (compound 810)
Compound 810 is prepared according to method i.
Raw material: NSC 87419.
preparation example 811:
ingenol-5,20-contracting acetone-3-(N-phenyl-carbamate) (compound 811)
Compound 811 is prepared according to method i.
Raw material: phenyl isocyanate.
preparation example 812:
ingenol-5,20-contracting acetone-3-(N-(indane-1-base)-carbamate) (compound 812)
Compound 812 is prepared according to method i.
Raw material: isocyanic ester-1-indane.
preparation example 813:
ingenol-5,20-contracting acetone-3-(3,3-DimethYI-pineridin-1-manthanoate) (compound 813)
Compound 813 is prepared according to method i.
Raw material: 3,3-DimethYI-pineridin-1-carbonyl chloride, it is prepared from 3,3-DimethYI-pineridin according to method f.
Preparation example 814:
ingenol-5,20-contracting acetone-3-(N-methyl-N-naphthane-1-base-carbamate) (compound 814)
Compound 814 is prepared according to method i.
Raw material: N-methyl-N-naphthane-1-base-urea chloride, it is prepared from N-methyl-N-(naphthane-1-base)-amine according to method f.
Preparation example 815:
ingenol-5,20-contracting acetone-3-(N-(2-cyano group-1-methyl-ethyl)-N-Methyl-carbamic acid ester) (compound 815)
Compound 815 is prepared according to method h.
Raw material: N-(2-cyano group-1-methyl-ethyl)-N-Methyl-amino formyl chloride, it is prepared from N-(2-cyano group-1-methyl-ethyl)-N-methyl-amine according to method f.
Preparation example 816:
ingenol-5,20-contracting acetone-3-(N-methyl-N-((S)-1-styroyl)-carbamate) (chemical combination thing 816)
Compound 816 is prepared according to method h.
Raw material: N-methyl-N-((S)-1-styroyl)-urea chloride, it is prepared from N-methyl-N-((S)-1-phenylethyl)-amine according to method f.
preparation example 817:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(Cvclopropvlmethvl)-carbamate) (chemical combination thing 817)
Compound 817 is prepared according to method h.
Raw material: N-(Cvclopropvlmethvl)-N-Methyl-amino formyl chloride, it is prepared from N-(Cvclopropvlmethvl)-N-methyl-amine according to method f.
1HNMR(300MHz,CDCl 3)δ6.03-6.02(m,1H),5,76-5.74(m,1H),5.45(s,1H),4.17-4.12(m,3H),3.97(s,1H),3.59(m,1H),3.30-3.13(m,2H),2.99(s,3H),2.56(bs,1H),2.34-2.25(m,1H),1.79-1.70(m,4H),1.45(s,3H),1.39(s,3H),1.29(m,1H),1.10(s,3H),1.05(s,3H),0.98(d,3H),0.94-0.86(m,1H),0.72-0.65(m,1H),0.53-0.48(m,2H),0.24-0.16(m,2H)。
preparation example 818:
ingenol-5,20-contracting acetone-3-(N-(the fluoro-phenyl of 3-)-N-Methyl-carbamic acid ester) (compound 818)
Compound 818 is prepared according to method j.
Raw material: N-(3-fluorophenyl)-N-Methyl-amino formyl chloride, it is prepared as tertiary amine from the fluoro-N-metlyl-phenylamine of 3-according to method f pyridine.
preparation example 819:
ingenol-5,20-contracting acetone-3-(N-(2,5-dimethyl pyrazole-3-base)-N-Methyl-carbamic acid ester) (compound 819)
Compound 819 is prepared according to method h.
Raw material: N-(2,5-dimethyl pyrazole-3-base)-N-Methyl-amino formyl chloride, it is from N, and 1,3-trimethylammonium-1H-pyrazoles-5-amine is prepared according to method f.
1HNMR(300MHz,CDCl 3)δ5.96(bs,1H),5.86(s,1H),5.76-5.74(m,1H),4.21-4.05(m,3H),3.95(s,1H),3.61(s,3H),3.20(s,3H),3.11(bs,1H),2.21(s,3H),1.84-1.74(m,4H),1.57(s,3H),1.45(s,3H),1.38(s,3H),1.07(s,3H),1.04(s,3H),0.90-0.83(m,1H),0.75(bd,3H),0.68-0.60(m,1H)。
preparation example 820:
((3,5-dimethyl is different for N-for ingenol-5,20-contracting acetone-3- azoles-4-base)-N-Methyl-carbamic acid ester) (compound 820)
Compound 820 is prepared according to method h.
[(3,5-dimethyl is different for raw material: N- azoles-4-base) methyl]-N-Methyl-amino formyl chloride, from 1-, (3,5-dimethyl is different for it azoles-4-base)-N-methyl-methylamine prepared according to method f.
1HNMR(300MHz,CDCl 3)δ6.05(s,1H),5.78-5.76(m,1H),5.46(s,1H),4.46(bs,1H),4.24-4.11(m,4H),3.98(s,1H),3.52(s,1H),2.78(s,3H),2.50(bs,1H),2.37(s,3H),2.30-2.21(m,4H),1.78(d,3H),1.77-1.68(m,1H),1.46(s,3H),1.41(s,3H),1.09(s,3H),1.05(s,3H),0.96(d,3H),0.94-0.89(m,1H),0.72-0.64(m,1H)。
preparation example 821:
ingenol-5,20-contracting acetone-3-(N-(1,5-dimethyl pyrazole-3-base)-N-Methyl-carbamic acid ester) (compound 821)
Compound 821 is prepared according to method h.
Raw material: N-(1,5-dimethyl pyrazole-3-base)-N-Methyl-amino formyl chloride, it is from N, and 1,5-trimethylpyrazol-3-amine is prepared according to method f.
1HNMR(300MHz,CDCl 3)δ5.96(bs,1H),5.86(s,1H),5.76-5.74(m,1H),5.42(s,1H),4.21-4.05(m,3H),3.95(s,1H),3.61(s,3H),3.20(s,3H),3.11(bs,1H),2.21(s,3H),2.12-2.02(m,1H),1.82-1.64(m,5H),1.45(s,3H),1.38(s,3H),1.07(s,3H),1.04(s,3H),0.90-0.85(m,1H),0.75(bs,3H),0.68-0.60(m,1H)。
preparation example 822:
ingenol-5,20-contracting acetone-3-(N-cyclopentyl-N-Methyl-carbamic acid ester) (compound 822)
Compound 822 is prepared according to method h.
Raw material: N-cyclopentyl-N-Methyl-amino formyl chloride, it is prepared from N-methylcyclohexylamine according to method f.
preparation example 823:
ingenol-5,20-contracting acetone-3-(N-cyclopropyl-N-Methyl-carbamic acid ester) (compound 823)
Compound 823 is prepared according to method h.
Raw material: N-cyclopropyl-N-Methyl-amino formyl chloride, it is prepared from N-methyl cyclopropylamine according to method f.
1HNMR(300MHz,CDCl 3)δ6.04-6.01(m,1H),5.77-5.74(m,1H),5.47(s,1H),4.17-4.12(m,3H),3.98(s,1H),3.52(s,1H),3.27(bs,1H),2.91(s,3H),2.65-2.57(m,2H),2.34-2.25(m,1H),1.80-1.70(m,4H),1.45(s,3H),1.39(s,1H),1.16-1.08(m,5H),1.05(s,3H),0.98(d,3H),0.94-0.87(m,1H),0.74-0.65(m,4H)。
preparation example 824:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(2-pyridyl)-carbamate) (compound 824)
Compound 824 is prepared according to method j.
Raw material: N-methyl-N-(2-pyridyl) urea chloride, it is prepared from N-picoline-2-amine according to method f.
1HNMR(300MHz,CDCl 3)δ8.38-8.36(m,1H),7.73-7.67(m,1H),7.43(d,1H),7.09-7.05(m,1H),6.00-5.98(m,1H),5.76-5.74(m,1H),5.71(s,1H),5.04(bs,1H),4.27-4.11(m,3H),3.95(s,1H),3.44(s,3H),2.30-2.20(m,2H),1.81(d,3H),1.70-1.60(m,1H),1.46(s,3H),1.39(s,3H),1.15(s,3H),1.06(s,3H),0.96-0.88(m,1H),0.79(d,3H),0.69-0.63(m,1H)。
preparation example 825:
ingenol-5,20-contracting acetone-3-(4-oxo-2,3-dihydroquinoline-1-manthanoate) (compound 825)
Compound 825 is prepared according to method j.
Raw material: 4-oxo-2,3-dihydroquinoline-1-carbonyl chloride, it is prepared from 2,3-dihydro-1H-quinoline-4-ketone according to method f.
preparation example 826:
ingenol-5,20-contracting acetone-3-(3,4-dihydro-2H-quinoline-1-manthanoate) (compound 826)
Compound 826 is prepared according to method j.
Raw material: 3,4-dihydro-2H-quinoline-1-carbonyl chloride, it is prepared from 1,2,3,4-tetrahydroquinoline according to method f.
1HNMR(300MHz,CDCl 3)δ7.68(d,1H),7.16-6.98(m,3H),6.03(d,1H),5.77-5.75(m,1H),5.58(s,1H),4.23-4.11(m,3H),4.00(s,1H),3.82-3.72(m,2H),3.39(s,1H),2.79(t,2H),2.46-2.41(m,1H),2.29-2.20(m,1H),2.01-1.92(m,2H),1.81(d,3H),1.71-1.63(m,1H),1.46(s,3H),1.41(s,3H),1.08(s,3H),1.04(s,3H),0.92-0.83(m,4H),0.71-0.63(m,1H)。
preparation example 827:
ingenol-5,20-contracting acetone-3-(indoline-1-manthanoate) (compound 827)
Compound 827 is prepared according to method j.
Raw material: indoline-1-carbonyl chloride, it is prepared from indoline according to method f.
1HNMR(300MHz,CDCl 3)δ7.87(bs,1H),7.22-7.09(m,2H),6.99-6.92(m,1H),6.09(bs,1H),5.79-5.77(m,1H),5.57(s,1H),4.25-4.12(m,3H),4.08-4.02(m,3H),3.50(bs,1H),3.18-3.10(m,2H),2.64bs,1H),2.34-2.24(m,1H),1.84(s,3H),1.79-1.70(m,1H),1.49(s,3H),1.43(s,3H),1.08(s,3H),1.05(s,3H),1.01(d,3H),0.94-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 828:
ingenol-5,20-contracting acetone-3-(azepan-1-manthanoate) (compound 828)
Compound 828 is prepared according to method j.
Raw material: azepan-1-carbonyl chloride, it is prepared from azepan according to method f.
1HNMR(300MHz,CDCl 3)δ6.03-6.01(m,1H),5.76-5.74(m,1H),5.47(s,1H),4.17-4.12(m,3H),3.97(s,1H),3.62(s,1H),3.49-3.27(m,4H),2.60-2.55(m,1H),2.35-2.26(m,1H),1.79-1.55(m,12H),1.46(s,3H),1.39(s,3H),1.10(s,3H),1.05(s,3H),0.98(d,3H),0.94-0.88(m,1H),0.72-0.64(m,1H)。
preparation example 829:
ingenol-5,20-contracting acetone-3-(N-(the chloro-phenyl of 4-)-N-Methyl-carbamic acid ester) (compound 829)
Compound 829 is prepared according to method j.
Raw material: N-(4-chloro-phenyl-)-N-Methyl-amino formyl chloride, it is prepared from the chloro-N-metlyl-phenylamine of 4-according to method f.
1HNMR(300MHz,CDCl 3)δ7.31(d,2H),7.20(d,2H),5.94(s,1H),5.76-5.73(m,1H),5.45(s,1H),4.21-4.07(m,3H),3.95(s,1H),3.29(s,3H),3.22(s,1H),3.14(d,1H),2.17-2.07(m,1H),1.75(d,3H),1.63-1.57(m,1H),1.45(s,3H),1.39(s,3H),1.08(s,3H),1.04(s,3H),0.90-0.83(m,1H),0.76(d,3H),0.69-0.61(m,1H)。
preparation example 830:
ingenol-5,20-contracting acetone-3-(N-(the fluoro-phenyl of 4-)-N-Methyl-carbamic acid ester) (compound 830)
Compound 830 is prepared according to method j.
Raw material: N-(4-fluorophenyl)-N-Methyl-amino formyl chloride, it is prepared from the fluoro-N-metlyl-phenylamine of 4-according to method f.
1HNMR(300MHz,CDCl 3)δ7.24-7.19(m,2H),7.06-6.98(m,2H),5.92(bs,1H),5.76-5.73(m,1H),5.45(s,1H),4.17-4.06(m,3H),3.95(s,1H),3.28(s,3H),3.23(bs,1H),3.13(d,1H),2.12-2.08(m,1H),1.74(d,3H),1.63-1.57(m,1H),1.45(s,3H),1.38(s,3H),1.08(s,3H),1.04(s,3H),0.92-0.83(m,1H),0.73(d,3H),0.69-0.61(m,1H)。
preparation example 831:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(2-methoxyl group-phenyl)-carbamate) (changes compound 831)
Compound 831 is prepared according to method j.
Raw material: N-(2-p-methoxy-phenyl)-N-Methyl-amino formyl chloride, it is prepared from 2-methoxy-. N-methyl-aniline according to method f.
preparation example 832:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(2-methylphenyl)-carbamate) (chemical combination thing 832)
Compound 832 is prepared according to method j.
Raw material: N-(2-aminomethyl phenyl)-N-Methyl-amino formyl chloride, it is prepared from 2-methyl-N-methyl-aniline according to method f.
preparation example 833:
ingenol-5,20-contracting acetone-3-(3-oxo-2,4-dihydro-quinoxaline-1-manthanoate) (compound 833)
Compound 833 is prepared according to method j.
Raw material: 3-oxo-2,4-dihydro-quinoxaline-1-carbonyl chloride, it is prepared from 3,4-dihydro-1H-quinoxaline-2-ketone according to method f.
1HNMR(300MHz,CDCl 3)δ8.82(s,1H),7.72(d,1H),7.15-7.01(m,2H),6.90(dd,1H),6.07-6.06(m,1H),5.80-5.78(m,1H),5.58(s,1H),4.47(d,1H),4.44(d,1H),4.25-4.09(m,3H),4.00(s,1H),3.39(s,1H),2.39(bs,1H),2.29-2.20(m,1H),1.81(d,3H),1.72-1.63(m,1H),1.45(s,3H),1.42(s,3H),1.08(s,3H),1.04(s,3H),0.92-0.84(m,4H),0.71-0.63(m,1H)。
preparation example 834:
ingenol-5,20-contracting acetone-3-(N-ethyl, N-phenyl-carbamate) (compound 834)
Compound 834 is prepared according to method j.
Raw material: N-ethyl, N-phenyl-urea chloride, it is prepared from N-ethyl-aniline according to method f. 1HNMR(300MHz,CDCl 3)δ7.38-7.32(m,2H),7.28-7.18(m,3H),5.89(s,1H),5.73-5.70(m,1H),5.46(s,1H),4.17-4.14(m,2H),4.04(bd,1H),3.94-3.93(m,1H),3.79-3.64(m,2H),3.16(bs,1H),2.04-1.78(m,2H),1.75(d,3H),1.54-1.49(m,1H),1.45(s,3H),1.37(s,3H),1.17(t,3H),1.06(s,3H),1.03(s,3H),0.90-0.81(m,1H),0.70-0.56(m,4H)。
preparation example 835:
ingenol-5,20-contracting acetone-3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) (compound 835)
Compound 835 is prepared according to method j.
Raw material: 2-(trifluoromethyl) tetramethyleneimine-1-carbonyl chloride, it is prepared from 2-(trifluoromethyl) tetramethyleneimine according to method f.
preparation example 836:
ingenol-5,20-contracting acetone-3-(3-azabicyclic [3.2.2] nonane-3-manthanoate) (compound 836)
Compound 836 is prepared according to method j.
Raw material: 3-azabicyclic [3.2.2] nonane-3-carbonyl chloride, it is prepared from 3-azabicyclic [3.2.2] nonane according to method f.
preparation example 837:
ingenol-5,20-contracting acetone-3-(2,3-dihydro-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate) (compound 837)
Compound 837 is prepared according to method j.
Raw material: 2,3-dihydro-Isosorbide-5-Nitrae-benzo piperazine-4-carbonyl chloride, it is from 2,3-dihydro-Isosorbide-5-Nitrae-benzo piperazine is prepared according to method f.
preparation example 838:
ingenol-5,20-contracting acetone-3-(N-(the fluoro-phenyl of 2-)-N-Methyl-carbamic acid ester) (compound 838)
Compound 838 is prepared according to method j.
Raw material: N-(the fluoro-phenyl of 2-)-N-Methyl-amino formyl chloride, it is prepared from the fluoro-N-metlyl-phenylamine of 2-according to method f.
1HNMR(300MHz,CDCl 3)δ7.29-7.21(m,2H),7.14-7.06(m,2H),5.87(bs,1H),5.73-5.72(m,1H),5.46(s,1H),4.16-4.14(m,2H),4.09-4.02(m,1H),3.93(s,1H),3.27(s,3H),3.21(s,1H),2.09-2.00(m,1H),1.73(bs,4H),1.52-1.45(m,4H),1.38(s,3H),1.07(s,3H),1.03(s,3H),0.88-0.82(m,1H),0.65-0.55(m,4H)。
preparation example 839:
ingenol-5,20-contracting acetone-3-(3-methyl-2,3-dihydros-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate) (change compound 839)
Compound 839 (mixture of diastereomer) is prepared according to method j.
Raw material: 3-methyl-2,3-dihydros-Isosorbide-5-Nitrae-benzo piperazine-4-carbonyl chloride, it is from 3-methyl-3,4-dihydro-2H-1,4-benzo piperazine is prepared according to method f.
preparation example 842:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(N-(t-butyloxycarbonyl)-4-piperidyl)- carbamate) (compound 842)
Compound 842 is prepared according to method j.
Raw material: 4-(chloroformyl (methyl) is amino) piperidines-1-t-butyl formate, it is prepared from 4-methylamino piperidines-1-t-butyl formate according to method f.
1HNMR(300MHz,CDCl 3)δ6.03-6.01(m,1H),5.77-5.74(m,1H),5.47(s,1H),4.27-4.10(m,5H),3.98(s,1H),3.49-3.38(m,2H),3.28(bs,1H),2.78(bs,4H),2.58-2.52(m,1H),2.32-2.24(m,1H),1.79-1.55(m,8H),1.46(s,9H),1.45(s,3H),1.39(s,3H),1.09(s,3H),1.05(s,3H),0.98(d,3H),0.94-0.87(m,1H),0.73-0.65(m,1H)。
preparation example 843:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(3-methylphenyl)-carbamate) (chemical combination thing 843)
Compound 843 is prepared according to method j.
Raw material: N-methyl-N-(3-methylphenyl)-urea chloride, it is prepared from N, 3-xylidine according to method f.
preparation example 844:
ingenol-5,20-contracting acetone-3-(3,4-dihydro-2H-quinoxaline-1-manthanoate) (compound 844)
Compound 844 is prepared according to method j.
Raw material: 3,4-dihydro-2H-quinoxaline-1-carbonyl chloride, it is prepared from 1,2,3,4-tetrahydroquinoxaline according to method f.
1HNMR(300MHz,CDCl 3)δ7.86(bd,1H),7.67(bs,1H),7.22-7.10(m,2H),6.07-6.06(m,1H),5.81-5.79(m,1H),5.57(s,1H),4.27-3.94(m,9H),3.34(s,1H),2.39(bs,1H),2.30-2.21(m,1H),1.82(d,3H),1.73-1.64(m,1H),1.47(s,3H),1.43(s,3H),1.09(s,3H),1.05(s,3H),0.92-0.84(m,4H),0.71-0.63(m,1H)。
preparation example 845:
ingenol-5,20-contracting acetone-3-(isoindoline-2-manthanoate) (compound 845)
Compound 845 is prepared according to method j.
Raw material: isoindoline-2-carbonyl chloride, it is prepared from isoindoline according to method f.
1HNMR(300MHz,CDCl 3)δ7.32-7.25(m,4H),6.07-6.06(m,1H),5.78-5.76(m,1H),5.51(s,1H),4.79-4.72(m,4H),4.20-4.13(m,3H),4.00(s,1H),3.59(s,1H),2.66-2.61(m,1H),2.35-2.25(m,1H),1.82(d,3H),1.81-1.72(m,1H),1.48(s,3H),1.41(s,3H),1.09(s,3H),1.04(s,3H),1.01(d.3H),0.94-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 846:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(tetrahydropyran-4-base methyl)-carbamate) (compound 846)
Compound 846 is prepared according to method j.
Raw material: N-methyl-N-(tetrahydropyran-4-base methyl)-urea chloride, it is prepared from N-methyl isophthalic acid-tetrahydropyran-4-base-methylamine according to method f.
preparation example 847:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(tetrahydropyran-4-base)-carbamate) (changes compound 847)
Compound 847 is prepared according to method j.
Raw material: N-methyl-N-(tetrahydropyran-4-base)-urea chloride, it is prepared from N-methyl tetrahydropyrans-4-amine according to method f.
1HNMR(300MHz,CDCl 3)δ6.04-6.03(m,1H),5.77-5.75(m,1H),5.48(s,1H),4.22-3.98(m,7H),3.45(bs,3H),2.82(s,3H),2.58-2.52(m,1H),2.33-2.24(m,1H),1.85-1.58(m,8H),1.45(s,3H),1.39(s,3H),1.09(s,3H),1.05(s,3H),0.99(d,3H),0.94-0.86(m,1H),0.73-0.65(m,1H)。
preparation example 848:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(3-methoxyl group-phenyl)-carbamate) (changes compound 848)
Compound 848 is prepared according to method j.
Raw material: N-methyl-N-(3-methoxyl group-phenyl)-urea chloride, it is prepared from N-methyl-3-methoxy-pllenylamine according to method f.
preparation example 849:
ingenol-5,20-contracting acetone-3-(N-cyclobutyl-N-Methyl-carbamic acid ester) (compound 849)
Compound 849 is prepared according to method h.
Raw material: N-cyclobutyl-N-Methyl-amino formyl chloride, it is prepared from N-methyl ring butylamine according to method f.
preparation example 850:
ingenol-5,20-contracting acetone-3-(N-allyl group-N-Methyl-carbamic acid ester) (compound 850)
Compound 850 is prepared according to method h.
Raw material: N-allyl group-N-Methyl-amino formyl chloride, it is prepared from N-methyl-prop-2-alkene-1-amine according to method f.
preparation example 851:
ingenol-5,20-contracting acetone-3-(N-methyl-N-Propargyl-carbamate) (compound 851)
Compound 851 is prepared according to method h.
Raw material: N-methyl-N-Propargyl-urea chloride, it is prepared from N-methyl-prop-2-alkynes-1-amine according to method f.
preparation example 852:
ingenol-5,20-contracting acetone-3-(N-methyl-N-(4-methylthiazol-2-base)-carbamate) (compound 852)
Compound 852 is prepared according to method j.
Raw material: N-methyl-N-(4-methylthiazol-2-base) urea chloride, it is prepared from N, 4-dimethylthiazole-2-amine according to method f.
preparation example 853:
ingenol-5,20-contracting acetone-3-(N-(4-cvano-phenyl)-N-Methyl-carbamic acid ester) (chemical combination thing 853)
Compound 853 is prepared according to method j.
Raw material: N-(4-cvano-phenyl)-N-Methyl-amino formyl chloride, it is prepared from N-methyl-4-cyano-phenyl amine according to method f.
embodiment 501:
ingenol 3-(5-methyl-3-(the fluoro-phenyl of the chloro-6-of 2-)-different azoles-4-manthanoate) (compound 501)
Compound 501 is prepared according to method e.
Raw material: compound 601.
1HNMR(300MHz,CDCl 3)δ7.42-7.34(m,1H),7.28-7.25(m,1H),7.09-7.03(m,1H),6.02(d,1H),5.85-5.84(m,1H),5.56(s,1H),4.46(d,1H),4.18-4.07(m,3H),3.99-3.97(m,1H),3.51(s,1H),2.83(s,3H),2.21-2.13(m,1H),1.88-1.82(m,1H),1.69-1.60(m,1H),1.64(d,3H),1.59(s,1H),1.03(s,3H),1.03(s,3H),0.90-0.82(m,1H),0.73(d,3H),0.67-0.59(m,1H)。
embodiment 502:
ingenol 3-(5-methyl-3-phenyl-different azoles-4-manthanoate) (compound 502)
Compound 502 is prepared according to method e.
Raw material: compound 602.
1HNMR(300MHz,CDCl 3)δ7.56-7.53(m,2H),7.48-7.38(m,3H),6.00(d,1H),5.94-5.93(m,1H),5.66(s,1H),4.31(d,1H),4.16-4.01(m,3H),3.98(d,1H),3.36(s,1H),2.77(s,3H),2.29-2.25(m,1H),2.05-1.96(m,1H),1.80-1.74(m,1H),1.74(d,3H),1.27(s,1H),1.03(s,3H),1.02(s,3H),0.90-0.82(m,1H),0.71(d,3H),0.65-0.57(m,1H)。
embodiment 503
ingenol 3-(1S-camphane acid esters) (compound 503)
Compound 503 is prepared according to method e.
Raw material: compound 603.
1HNMR(300MHz,CDCl 3)δ6.09-6-05(m,2H),5.69(s,1H),4.28(d,1H),4.21-4.12(m,3H),4.03(d,1H),3.62(s,1H),2.55-2.42(m,2H),2.31-2.21(m,2H),2.12-2.03(m,1H),1.99-1.89(m,1H),1.80(d,3H),1.77-1.65(m,2H),1.13(s,3H),1.09(s,6H),1.05(s,3H),0.98-0.86(m,7H),0.74-0.66(m,1H)。
embodiment 504
ingenol 3-(3-Phenyltriazole-4-manthanoate) (compound 504)
Compound 504 is prepared according to method e.
Raw material: compound 604.
1HNMR(300MHz,CDCl 3)8.28(s,1H),7.55-7.49(m,5H),6.05(m,1H),6.02-6.01(m,1H),5.70(s,1H),4.69(d,1H),4.15-4.10(m,3H),4.01(m,1H),3.55(s,1H),2.40-2.37(m,1H),2.24-2.15(m,2H),1.75(d,3H),1.74-1.64(m,1H),1.04(s,3H),1.04(s,3H),0.92-0.85(m,4H),0.71-0.63(m,1H)。
embodiment 505
ingenol 3-(2-phenylpyrazole-3-manthanoate) (compound 505)
Compound 505 is prepared according to method e.
Raw material: compound 605.
1HNMR(300MHz,DMSO-d 6)7.82(d,1H),7.49-7.45(m,5H),7.03(d,1H),5.86-5.83(m,2H),5.81(s,1H),5.35(d,1H),5.14(s,1H),4.62(t,1H),4.14-4.10(m,1H),3.91-3.86(m,2H),3.58(d,1H),2.28-2.10(m,2H),1.70(d,3H),1.69-1.58(m,1H),1.02(s,3H),1.01(s,3H),0.80-0.70(m,4H),0.62-0.54(m,1H)。
embodiment 506
ingenol 3-(1-methyl-benzdiazole-3-formic acid ester) (compound 506)
Compound 506 is prepared according to method e.
Raw material: compound 606.
1HNMR(300MHz,DMSO-d 6)8.15-8.12(m,1H),7.80-7.77(m,1H),7.52-7.45(m,1H),7.34-7.29(m,1H),6,00(m,1H),5.99(s,1H),5.90-5.89(m,1H),5.51(d,1H),5.26(s,1H),4.68(t,1H),4.22-4.27(m,1H),4.17(s,3H),3.99-3.89(m,2H),3.72(d,1H),2.77-2.70(m,1H),2.39-2.30(m,1H),1.79(d,3H),1.72-1.64(m,1H),1.04(s,6H),0.95(d,3H),0.85-0.77(m,1H),0.67-0.59(m,1H)。
embodiment 507
ingenol 3-(3-ethyl-5-methyl-different azoles-4-manthanoate) (compound 507)
Compound 507 is prepared according to method e.Obtaining compound 507, is amorphous compound.
Raw material: compound 607.
1HNMR(300MHz,CDCl 3)6.13-6.12(m,1H),6.09-6.07(m,1H),5.69(s,1H),4.65(bs,1H),4.24-4.15(m,3H),4.11(s,1H),3.68(s,1H),2.88(q,2H),2.66(s,3H),2.59-2.54(m,1H),2.34-2.15(m,2H),1.83(d,3H),1.79-1.71(m,1H),1.29(t,3H),1.07(s,3H),1.05(s,3H),1.01(d,3H),0.96-0.90(m,1H),0.74-0.66(m,1H)。
embodiment 508
ingenol 3-(3-methyl-5-methyl-different azoles-4-manthanoate) (compound 508)
Compound 508 is prepared according to method e.
Raw material: compound 608.
1HNMR(300MHz,CDCl 3)6.12(m,1H),6.08-6.07(m,1H),5.69(s,1H),4.74(m,1H),4.23-4.16(m,3H),4.11(s,1H),3.71(s,1H),2.66(s,3H),2.59-2.54(m,1H),2.43(s,3H),2.36-2.26(m,2H),1.84-1.71(m,4H),1.07(s,3H),1.06(s,3H),1.01(d,3H),0.95-0.89(m,1H),0.74-0.66(m,1H)。
embodiment 509
ingenol 3-(1-skatole-3-manthanoate) (compound 509)
Compound 509 is prepared according to method e.
Raw material: compound 609.
1HNMR(300MHz,CDCl 3)8.13-8.10(m,1H),7.81(s,1H),7.39-7.28(m,3H),6.10(m,1H),6.06(d,1H),5.69(s,1H),4.43(bs,1H),4.17-4.12(m,4H),3.86(s,3H),3.69(s,1H),2.68-2.63(m,1H),2.41(bs,1H),2.29-2.20(m,1H),1.87(d,3H),1.80-1.71(m,1H),1.05-1.03(m,9H),0.99-0.93(m,1H),0.73-0.65(m,1H)。
embodiment 510
ingenol 3-(3-tolylthiophene-2-manthanoate) (compound 510)
Compound 510 is prepared according to method e.
Raw material: compound 610.
1HNMR(300MHz,CDCl 3)7.57(d,1H),7.45-7.35(m,5H),7.09(d,1H),5.96-5.97(m,1H),5.91(d,1H),5.64(s,1H),4.30(d,1H),4.04-3.94(m,4H),3.31(s,1H),2.59(bs,1H),2.10-2.04(m,2H),1.77(d,3H),1.64-1.55(m,1H),1.01(s,3H),0.97(s,3H),0.90-0.82(m,4H),0.66-0.58(m,1H)。
embodiment 511
(5-phenyl is different for ingenol 3- azoles-3-manthanoate) (compound 511)
Compound 511 is prepared according to method e.
Raw material: compound 611.
1HNMR(300MHz,CDCl 3)7.82-7.77(m,2H),7.51-7.47(m,3H),6.92(s,1H),6.15-6.14(m,1H),6.07(d,1H),5.89(s,1H),4.47(d,1H),4.20-4.09(m,4H),3.86(s,1H),2.68-2.60(m,2H),2.29-2.23(m,1H),1.87-1.76(m,4H),1.06(s,3H),1.05-1.02(m,6H),1.00-0.89(m,1H),0.74-0.67(m,1H).
embodiment 512
ingenol 3-(isoquinoline 99.9-1-manthanoate) (compound 512)
Compound 512 is prepared according to method e.By title compound by purification by flash chromatography (methylene chloride/methanol 98:2 → methylene chloride/methanol 95:5).
Raw material: compound 612.
1HNMR(300MHz,CDCl 3)δ8.73(d,1H),8.55(d,1H),7.93-7.85(m,2H),7.81-7.71(m,2H),6.16-6.15(m,1H),6.09-6.07(m,1H),6.04(s,1H),5.67(s,1H),5.30(s,1H),4.29-4.18(m,3H),3.60(d,1H),2.68-2.63(m,1H),2.45-2.36(m,2H),1.94(d,3H),1.90-1.82(m,1H),1.17(s,3H),1.09(s,3H),1.02-0.95(m,4H),0.78-0.70(m,1H)。
embodiment 513
ingenol 3-(quinoline-4-manthanoate) (compound 513)
Compound 513 is prepared according to method e.By title compound by purification by flash chromatography (methylene chloride/methanol 98:2 → methylene chloride/methanol 95:5).
Raw material: compound 613.
1HNMR(300MHz,CDCl 3)δ9.04(d,1H),8.84-8.80(m,1H),8.20-8.17(m,1H),7.88(d,1H),7.79-7.75(m,1H),7.68-7.62(m,1H),6.17(m,1H),6.10(d,1H),5.94(s,1H),4.76(d,1H),4.29-4.19(m,4H),3.84(s,1H),2.67-2.61(m,1H),2.40-2.31(m,2H),1.88(d,3H),1.85-1.76(m,1H),1.08(s,3H),1.06(s,3H),1.01(d,3H),0.98-0.92(m,1H),0.76-0.68(m,1H).
embodiment 514
ingenol 3-(cinnolines-4-manthanoate) (compound 514)
Compound 514 is prepared according to method e.By title compound by purification by flash chromatography (methylene chloride/methanol 98:2 → methylene chloride/methanol 95:5).
Raw material: compound 614.
1HNMR(300MHz,DMSO-d 6)δ9.65(s,1H),8.89-8.86(m,1H),8.65-8.61(m,1H),8.10-8.00(m,2H),6.14(s,1H),6.04(d,1H),5.93-5.92(m,1H),5.78(s,1H),5.59(d,1H),4.69(t,1H),4.28-4.23(m,1H),4.04-3.92(m,2H),3.73(d,1H),2.64-2.57(m,1H),2.45-2.37(m,1H),1.83(d,3H),1.80-1.71(m,1H),1.08(s,3H),1.05(s,3H),0.93(d,3H),0.85-0.79(m,1H),0.69-0.61(m,1H)。
embodiment 515
ingenol 3-(3-phenylimidazole-4-manthanoate) (compound 515)
Compound 515 is prepared according to method e.By title compound by purification by flash chromatography (methylene chloride/methanol 98:2 → methylene chloride/methanol 95:5).
Raw material: compound 615.
1HNMR(300MHz,CDCl 3)δ7.89(d,1H),7.68(d,1H),7.49-7.44(m,3H),7.37-7.32(m,2H),6.00-5.98(m,2H),5.61(s,1H),5.30(s,1H),4.53(d,1H),4.14-4.10(m,3H),3.98(bs,1H),3.53(s,1H),2.65(bs,1H),2.30-2.15(m,2H),1.73-1.65(m,4H),1.04(s,6H),0.93-0.85(m,4H),0.71-0.63(m,1H)。
embodiment 516
ingenol 3-(5-phenyl azoles-4-manthanoate) (compound 516)
Compound 516 is prepared according to method e.
Raw material: compound 616.
1HNMR(300MHz,DMSO-d 6)δ8.56(s,1H),7.92-7.88(m,2H),7.53-7.48(m,3H),5.92(s,1H),5.90(d,1H),5.86-5.85(m,1H),5.42(d,1H),5.00(s,1H),4.63(t,1H),4.14-4.08(m,1H),3.98-3.85(m,2H),3.64(d,1H),2.25-2.10(m,2H),1.75(d,3H),1.51-1.44(m,1H),1.01(s,3H),0.99(s,3H),0.77-0.70(m,4H),0.58-0.50(m,1H)。
embodiment 517
ingenol 3-(1,2-benzo azoles-3-manthanoate) (compound 517)
Compound 517 is prepared according to method e.
Raw material: compound 617.
1HNMR(300MHz,CDCl 3)8.17-8.14(m,1H),7.70-7.61(m,2H),7.47-7.42(m,1H),6.19-6.18(m,1H),6.09-6.08(m,1H),5.97(s,1H),4.47(d,1H),4.26-4.16(m,3H),4.12(bs,1H),3.80(s,1H),2.73-2.65(m,1H),2.32-2.23(m,2H),1.90(d,3H),1.86-1.74(m,1H),1.06-1.03(m,9H),0.97-0.90(m,1H),0.75-0.67(m,1H)。
embodiment 518
ingenol 3-(3-sec.-propyl-5-methyl-different azoles-4-manthanoate) (compound 518)
Compound 518 is prepared according to method e.
Raw material: compound 618.
1HNMR(300MHz,CDCl 3)6.13-6.12(m,1H),6.08-6.07(d,1H),5.69(s,1H),4.67(d,1H),4.23-4.18(m,3H),4.11(bs,1H),3.69(s,1H),3.44(septet,1H),2.65(s,3H),2.60-2.51(m,1H),2.35-2.22(m,2H),1.83(d,3H),1.79-1.70(m,1H),1.33(d,3H),1.32(d,3H),1.07(s,3H),1.06(s,3H),1.00(d,3H),0.96-0.86(m,1H),0.74-0.66(m,1H)。
embodiment 519
ingenol 3-(3-(2-p-methoxy-phenyl)-5-methyl-different azoles-4-manthanoate) (compound 519)
Compound 519 is prepared according to method e.
Raw material: compound 619.
1HNMR(300MHz,CDCl 3)7.46-7.36(m,2H),7.04(dt,1H),6.95(d,1H),6.01(d,1H),5.91-5.90(m,1H),5.69(s,1H),4.14-4.06(m,2H),3.98(dd,1H),3.91(d,1H),3.82(d,1H),3.77(s,3H),3.26(s,1H),2.75(s,3H),2.26-2.21(m,1H),1.99-1.89(m,1H),1.72(d,3H),1.65-1.61(m,1H),1.55-1.46(m,1H),1.04(s,3H),1.04(s,3H),0.90-0.83(m,1H),0.74(d,3H),0.65-0.57(m,1H)。
embodiment 520
ingenol 3-(the bromo-2-methyl pyrazole of 4--3-manthanoate) (compound 520)
Compound 520 is prepared according to method e.
Raw material: compound 620.
1HNMR(300MHz,CDCl 3)7.52(s,1H),6.15-6.14(m,1H),6.08(d,1H),5.84(s,1H),5.30(s,1H),4.21-4.05(m,7H),3.85(s,1H),2.77-2.73(m,1H),2.30-2.17(m,2H),1.87(d,3H),1.80-1.72(m,1H),1.08(s,3H),1.06(s,3H),1.00(d,3H),0.97-0.90(m,1H),0.75-0.67(m,1H)。
embodiment 521
ingenol 3-(4-bromo-2-ethyl-pyrazoles-3-manthanoate) (compound 521)
Compound 521 is prepared according to method e.
Raw material: compound 621.
1HNMR(300MHz,CDCl 3)7.54(s,1H),6.15-6.13(m,1H),6.09-6.07(m,1H),5.86(s,1H),4.68-4.55(m,2H),4.24-4.13(m,4H),4.07(d,1H),3.87(s,1H),2.77-2.70(m,1H),2.32-2.20(m,2H),1.87(d,3H),1.80-1.71(m,1H),1.44(t,3H),1.09(s,3H),1.06(s,3H),0.98(d,3H),0.97-0.90(m,1H),0.75-0.67(m,1H)。
embodiment 522
ingenol 3-(4-chloro-2-methyl-pyrazoles-3-manthanoate) (compound 522)
Compound 522 is prepared according to method e.
Raw material: compound 622.
1HNMR(300MHz,CDCl 3)7.48(s,1H),6.14-6.13(m,1H),6.09-6.06(m,1H),5.84(s,1H),4.23-4.11(m,7H),4.07-4.05(d,1H),3.83(s,1H),2.73-2.64(m,1H),2.31-2.20(m,2H),1.87(d,3H),1.81-1.72(m,1H),1.08(s,3H),1.06(s,3H),1.00(d,3H),0.97-0.87(m,1H),0.75-0.67(m,1H)。
embodiment 523
ingenol 3-(5-bromo pyrimi piperidine-4-manthanoate) (compound 523)
Compound 523 is prepared according to method e.
Raw material: compound 623.
1HNMR(300MHz,CDCl 3)9.21(s,1H),9.02(s,1H),6.16-6.14(m,1H),6.09-6.07(m,1H),5.96(s,1H),4.22-4.12(m,4H),4.06-4.04(m,2H),2.57-2.52(m,1H),2.33-2.24(m,2H),1.90(d,3H),1.88-1.79(m,1H),1.10(s,3H),1.06(s,3H),0.98-0.90(m,4H),0.75-0.67(m,1H)。
embodiment 524
ingenol 3-(3-bromopyridine-2-manthanoate) (compound 524)
Compound 524 is prepared according to method e.
Raw material: compound 624.
1HNMR(300MHz,CDCl 3)8.58(dd,1H),8.03(dd,1H),7.34(dd,1H),6.11-6.13(m,1H),6.07-6.05(m,1H),5.98(s,1H),4.74(d,1H),4.21-4.15(m,3H),4.00(d,1H),3.69(d,1H),2.56-2.48(m,2H),2.34-2.24(m,1H),1.91(d,3H),1.83-1.74(m,1H),1.12(s,3H),1.05(s,3H),0.98-0.92(m,4H),0.75-0.67(m,1H)。
embodiment 525
ingenol 3-(5-methylthiazol-4-manthanoate) (compound 525)
Compound 525 is prepared according to method e.
Raw material: compound 625.
1HNMR(300MHz,CDCl 3)8.59(s,1H),6.10-6.05(m,2H),5.70(s,1H),4.21-4.14(m,4H),4.04(s,2H),2.81(s,3H),2.66-2.59(m,2H),2.32-2.23(m,1H),1.86(d,3H),1.83-1.74(m,1H),1.09(s,3H),1.06(s,3H),1.00(d,3H),0.98-0.91(m,1H),0.75-0.67(m,1H)。
embodiment 526
ingenol 3-(the chloro-1-methyl pyrazole of 4--3-manthanoate) (compound 526)
Compound 526 is prepared according to method e.
Raw material: compound 626.
1HNMR(300MHz,CDCl 3)7.47(s,1H),6.10-6.05(m,2H),5.82(s,1H),4.18-4.12(m,3H),4.04(d,1H),3.96(s,3H),3.87(s,1H),3.79(d,1H),2.70-2.63(m,1H),2.34-2.21(m,2H),1.87(d,3H),1.82-1.73(m,1H),1.09(s,3H),1.05(s,3H),1.00(d,3H),0.98-0.92(m,1H),0.74-0.67(m,1H)。
embodiment 527
ingenol 3-(2,4-dimethylthiazole-5-manthanoate) (compound 527)
Compound 527 is prepared according to method e.
Raw material: compound 627.
1HNMR(300MHz,CDCl 3)6.10-6-08(m,1H),6.07-6.05(m,1H),5.69(s,1H),4.61(d,1H),4.21-4.15(m,3H),4.08(s,1H),3.62(d,1H),2.70(s,3H),2.69(s,3H),2.62-2.54(m,2H),2.32-2.25(m,1H),1.82(d,3H),1.80-1.73(m,1H),1.07(s,3H),1.05(s,3H),1.01(d,3H),0.97-0.90(m,1H),0.74-0.66(m,1H)。
embodiment 528
ingenol 3-(2,5-dimethyl azoles-4-manthanoate) (compound 528)
Compound 528 is prepared according to method e.
Raw material: compound 628.
1HNMR(300MHz,CDCl 3)6.03-6.00(m,2H),5.74(s,1H),4.51-4.47(m,2H),4.25-4.10(m,3H),4.02(bs,1H),3.55(s,1H),2.59(s,3H),2.57-2.54(m,1H),2.44(s,3H),2.31-2.22(m,1H),1.81(d,3H),1.79-1.71(m,1H),1.07(s,3H),1.05(s,3H),0.98(d,3H),0,95-0.88(m,1H),0.73-0.65(m,1H)。
embodiment 529
ingenol 3-(2,4-dimethyl furan-3-manthanoate) (compound 529)
Compound 529 is prepared according to method e.Obtaining compound 529, is amorphous compound.
Raw material: compound 629.
1HNMR(300MHz,CDCl 3)7.06(q,1H),6.09-6.06(m,2H),5.62(m,1H),4.50(d,1H),4.19-4.13(m,3H),4.12-4.09(m,1H),3.66(s,1H),2.61-2.55(m,1H),2.54(s,3H),2.39(t,1H),2.32-2.23(m,1H),2.12(d,3H),1.83(d,3H),1.79-1.70(m,1H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.98-0.90(m,1H),0.73-0.65(m,1H)。
embodiment 530
(3,5-diethyl is different for ingenol 3- azoles-4-manthanoate) (compound 530)
Compound 530 is prepared according to method e.
Raw material: compound 630.
1hNMR (300MHz, CDCl 3) 6.14-6.12 (m, 1H), 6.08-6.07 (m, 1H); 5.70 (s, 1H), 4.68 (d, 1H); 4.23-4.18 (m, 3H), 4.12-4.11 (m, 1H); 3.69 (s, 1H), 3.09 (dq, 2H); 2.89 (dq, 2H), 2.59-2.52 (m; 1H), 2.35-2.25 (m, 2H); 1.83 (d, 3H), 1.79-1.70 (m; 1H), 1.31 (t, 3H); 1.29 (t, 3H), 1.07 (s; 3H), 1.05 (s, 3H); 1.01 (d, 3H), 0.96-0.89 (m; 1H), 0.74-0.65 (m, 1H); Observe 0.5mol ethyl acetate: 4.12 (q, 0.5x2H), 2.04 (s, 0.5x3H), 1.26 (t, 0.5x3H).
embodiment 531
ingenol 3-(1H-indoles-7-manthanoate) (compound 531)
Compound 531 is prepared according to method e.
Raw material: compound 631.
1HNMR(300MHz,CDCl 3)10.13(bs,1H),7.90-7.85(m,2H),7.31-7.29(m,1H),7.18(t,1H),6.62-6.60(m,1H),6.13-6.12(m,1H),6.08(d,1H),5.84(s,1H),4.69(d,1H),4.27-4.16(m,4H),3.85(s,1H),2.71-2.66(m,1H),2.43(bs,1H),2.37-2.28(m,1H),1.88(d,3H),1.85-1.76(m,1H),1.08(s,3H),1.06(s,3H),1.04(d,3H),0.98-0.92(m,1H),0.76-0.68(m,1H)。
embodiment 532
ingenol 3-(the 2-tertiary butyl-5-methyl pyrazole-3-manthanoate) (compound 532)
Compound 532 is prepared according to method e.
Raw material: compound 632.
1HNMR(300MHz,CDCl 3)6.65(s,1H),6.09-6.06(m,2H),5.69(s,1H),4.40(d,1H),4.20-4.13(m,3H),4.08(d,1H),3.54(s,1H),2.60-2.55(m,1H),2.33-2.24(m,5H),1.82(d,3H),1.80-1.75(m,1H),1.70(s,9H),1.08(s,3H),1.06(s,3H),1.01(d,3H),0.98-0.91(m,1H),0.75-0.67(m,1H)。
embodiment 533
ingenol 3-(the 5-tertiary butyl-2-methyl pyrazole-3-manthanoate) (compound 533)
Compound 533 is prepared according to method e.
Raw material: compound 633.
1HNMR(300MHz,CDCl 3)6.63(s,1H),6.12-6.10(m,1H),6.08-6.06(d,1H),5.71(s,1H),4.57(d,1H),4.20-4.15(m,3H),4.13(s,3H),4.10(d,1H),3.62(s,1H),2.61-2.55(m,1H),2.40(t,1H),2.32-2.23(m,1H),1.83(d,3H),1.82-1.73(m,1H),1.31(s,9H),1.07(s,3H),1.05(s,3H),1.03(d,3H),0.97-0.91(m,1H),0.75-0.67(m,1H)。
embodiment 534
ingenol 3-(6-Methylimidazole is [2,1-b] thiazole-5-manthanoate also) (compound 534)
Compound 534 is prepared according to method e.
Raw material: compound 634.
1HNMR(300MHz,CDCl 3)8.09(d,1H),6.93(d,1H),6.15-6.13(m,1H),6.08(d,1H),5.73(s,1H),4.24-4.17(m,4H),4.14-4.13(m,1H),3.80(bs,1H),2.63-2.59(m,5H),2.33-2.25(m,1H),1.86(d,3H),1.80-1.71(m,1H),1.06(s,3H),1.05(s,3H),1.02(d,3H),0.97-0.90(m,1H),0.74-0.66(m,1H)。
embodiment 535
ingenol 3-(glyoxal ethyline is [1,2-a] Nicotinicum Acidum ester also) (compound 535)
Compound 535 is prepared according to method e.
Raw material: compound 635.
1HNMR(300MHz,CDCl 3)9.37(d,1H),8.09(s,1H),7.74(d,1H),7.49-7.43(m,1H),7.06-7.01(m,1H),6.19-6.08(m,2H),5.80(s,1H),4.33-4.17(m,4H),3.43(bs,2H),2.72-2.63(m,4H),2.33-2.24(m,1H),1.88(d,3H),1.80-1.71(m,1H),1.06(s,3H),1.05(s,3H),1.03(d,3H),0.97-0.85(m,1H),0.75-0.67(m,1H)。
embodiment 536
ingenol 3-(2,4,5-trimethylammonium furans-3-manthanoate) (compound 536)
Compound 536 is prepared according to method e.
Raw material: compound 636.
1HNMR(300MHz,CDCl 3)6.07-6.04(m,2H),5.63(s,1H),4.65(d,1H),4.20-4.14(m,3H),4.09(d,1H),3.71(s,1H),2.80(t,1H),2.62-2.56(m,1H),2.50(s,3H),2.32-2.23(m,1H),2.17(s,3H),2.04(s,3H),1.82(d,3H),1.78-1.69(m,1H),1.06(s,3H),1.05(s,3H),0.98(d,3H),0.94-0.90(m,1H),0.72-0.65(m,1H)。
embodiment 537
ingenol 3-(3 methyl thiophene-2-manthanoate) (compound 537)
Compound 537 is prepared according to method e.
Raw material: compound 637.
1HNMR(300MHz,CDCl 3)7.42(d,1H),6.94(d,1H),6.09-6.07(m,1H),6.06-6.04(m,1H),5.71(s,1H),4.49(bs,1H),4.22-4.12(m,3H),4.09-4.08(m,1H),3.63(s,1H),2.70-2.60(m,2H),2.57(s,3H),2.32-2.22(m,1H),1.84(d,3H),1.81-1.72(m,1H),1.05(s,3H),1.04(s,3H),1.02(d,3H),0.96-0.90(m,1H),0.73-0.66(m,1H)。
embodiment 538
ingenol 3-(2-methyl-4-(piperidino) pyrazoles-3-manthanoate) (compound 538)
Compound 538 is prepared according to method e.
Raw material: compound 638.
1HNMR(300MHz,CDCl 3)7.36(s,1H),6.10-6.07(m,2H),5.69(s,1H),4.23-4.13(m,3H),4.10(s,3H),4.01(s,1H),2.97-2.82(m,4H),2.68-2.62(m,1H),2.31-2.22(m,1H),1.87(d,3H),1.84-1.59(m,8H),1.55-1.49(m,2H),1.10(s,3H),1.05(s,3H),0.99(d,3H),0.98-0.94(m,1H),0.74-0.66(m,1H)。
embodiment 539
ingenol 3-(the chloro-5-sec.-propyl-4-thiazolecarboxylic acid ester of 2-) (compound 539)
Compound 539 is prepared according to method e.
Raw material: compound 639.
1HNMR(300MHz,CDCl 3)6.09-6.05(m,2H),5.77(s,1H),4.19-4.08(m,5H),4.04-3.98(m,2H),2.64-2.55(m,2H),2.33-2.24(m,1H),1.85(d,3H),1.83-1.71(m,1H),1.34(d,3H),1.32(d,3H),1.10(s,3H),1.06(s,3H),1.01(d,3H),0.97-0.91(m,1H),0.75-0.67(m,1H)。
embodiment 540
ingenol 3-(chloro-2, the 5-Dimethyl-pyrazol-3-manthanoate of 4-) (compound 540)
Compound 540 is prepared according to method e.
Raw material: compound 640.
1HNMR(300MHz,CDCl 3)6.14-6.12(m,1H),6.08-6.06(m,1H),5.83(s,1H),4.21-4.04(m,8H),3.85(s,1H),2.73-2.68(m,1H),2.42(bs,1H),2.30-2.21(m,4H),1.86(d,3H),1.81-1.72(m,1H),1.08(s,3H),1.06(s,3H),1.00(d,3H),0.97-0.90(m,1H),0.75-0.67(m,1H)。
embodiment 541
ingenol 3-(1,2,4-trimethylammonium pyrroles-3-manthanoate) (compound 541)
Compound 541 is prepared according to method e.
Raw material: compound 641.
1HNMR(300MHz,CDCl 3)6.29(m,1H),6.06-6.03(m,2H),5.55(s,1H),4.51(d,1H),4.16-4.08(m,4H),3.68(s,1H),3.47(s,3H),2.63-2.52(m,2H),2.47(s,3H),2.29-2.20(m,1H),2.18(s,3H),1.83(d,3H),1.77-1.68(m,1H),1.07(s,3H),1.04(s,3H),0.98(d,3H),0.99-0.93(m,1H),0.72-0.64(m,1H)。
embodiment 542
ingenol 3-(1,3,5-trimethylammonium pyrroles-2-manthanoate) (compound 542)
Compound 542 is prepared according to method e.
Raw material: compound 642.
1HNMR(300MHz,CDCl 3)6.06-6.05(m,2H),5.81(s,1H),5.59(s,1H),4.44(d,1H),4.17-4.08(m,4H),3.77(s,3H),3.70(s,1H),2.63-2.57(m,1H),2.44(t,1H),2.29-2.24(m,4H),2.21(s,3H),1.83(d,3H),1.78-1.69(m,1H),1.07(s,3H),1.05(s,3H),0.98(d,3H),0.95-0.90(m,1H),0.72-0.65(m,1H)。
embodiment 543
ingenol 3-(1-ethyl-3,5-dimethyl pyrrole-2-manthanoate) (compound 543)
Compound 543 is prepared according to method e.
Raw material: compound 643.
1HNMR(300MHz,CDCl 3)6.07-6.05(m,2H),5.81(s,1H),5.58(s,1H),4.43(d,1H),4.32-4.24(m,2H),4.17-4.09(m,4H),3.67(s,1H),2.62-2.57(m,1H),2.36-2.34(m,1H),2.30-2.20(m,7H),1.84(d,3H),1.78-1.69(m,1H),1.27(t,3H),1.07(s,3H),1.05(s,3H),0.98(d,3H),0.95-0.90(m,1H),0.72-0.65(m,1H)。
embodiment 544
ingenol 3-(1-t-butyloxycarbonyl-3,3-dimethyl pyrrolidine-2-manthanoate) (compound 544)
Compound 544 is prepared according to method e.
Raw material: compound 644.
1hNMR (300MHz, CDCl 3) display compound mixture.
embodiment 545
ingenol 3-((2S)-1-Phenylpyrrolidine-2-manthanoate) (compound 545)
Compound 545 is according to method e preparation, and change as follows: replaced by tetrahydrofuran (THF) methyl alcohol, the reaction times under room temperature is 0.5h.
Raw material: compound 645.
1HNMR(300MHz,CDCl 3)7.27-7.21(m,2H),6.72(t,1H),6.54(d,2H),6.01-5.99(m,1H),5.96(d,1H),5.68(s,1H),4.43(dd,1H),4.13-4.03(m,2H),3.88-3.83(m,2H),3.49-3.37(m,3H),2.70(s,1H),2.46-2.39(m,1H),2.28-2.20(m,2H),2.13-1.96(m,3H),1.75(d,3H),1.68-1.57(m,1H),1.49-1.40(m,1H),1.03(s,3H),0.96(s,3H),0.89-0.81(m,4H),0.62-0.54(m,1H)。
embodiment 546
ingenol 3-(1-sec.-propyl-3,5-Dimethyl-pyrazol-4-manthanoate) (compound 546)
Compound 546 is prepared according to method e.
Raw material: compound 646.
1hNMR (300MHz, CDCl 3) 6.07-6.04 (m, 2H), 5.61 (s, 1H), 4.63 (d, 1H), 4.43 (septet, 1H), 4.19-4.10 (m, 4H), 3.70 (s, 1H), 2.70 (t, 1H), 2.62-2.58 (m, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.31-2.22 (m, 1H), 1.83 (d, 3H), 1.79-1.70 (m, 1H), 1.46 (d, 6H), 1.07 (s, 3H), 1.04 (s, 3H), 0.99 (d, 3H), 0.97-0.90 (d, 1H), 0.73-0.65 (m, 1H).
embodiment 547
ingenol 3-(5-ethyl-3-sec.-propyl-different azoles-4-manthanoate) (compound 547)
Compound 547, according to method e preparation, changes as follows: replaced by tetrahydrofuran (THF) methyl alcohol and reaction times is at room temperature 0.5h.
Raw material: compound 647.
1HNMR(300MHz,CDCl 3)6.13-6.12(m,1H),6.08-6.06(d,1H),5.71(s,1H),4.75(d,1H),4.23-4.17(m,3H),4.13-4.10(m,1H),3.70(s,1H),3.45(septet,1H),3.12-3.04(m,2H),2.58-2.46(m,2H),2.35-2.26(m,1H),1.83(d,3H),1.79-1.70(m,1H),1.33(d,3H),1.32(d,3H),1.30(t,3H),1.07(s,3H),1.06(s,3H),1.00(d,3H),0.96-0.89(m,1H),0.74-0.66(m,1H)。
embodiment 548
ingenol 3-(2-methyl-benzdiazole-3-formic acid ester) (compound 548)
Compound 548, according to method e preparation, changes as follows: replaced by tetrahydrofuran (THF) methyl alcohol and reaction times is at room temperature 0.5h.
Raw material: compound 648.
1HNMR(300MHz,CDCl 3)7.97-7.94(m,1H),7.81-7.78(m,1H),7.39-7.34(m,1H),7.31-7.26(m,1H),6.22-6.21(m,1H),6.10-6.08(m,1H),5.86(s,1H),4.75(d,1H),4.54(s,3H),4.26-4.18(m,4H),3.80(s,1H),2.74-2.69(m,1H),2.32-2.22(m,2H),1.91(d,3H),1.75-1.67(m,1H),1.07(d,3H),1.05(s,3H),1.04(s,3H),0.97-0.90(m,1H),0.73-0.65(m,1H)。
embodiment 549
ingenol 3-(5-methyl-3-the tertiary butyl-different azoles-4-manthanoate) (compound 549)
Compound 549 is prepared according to method e.
Raw material: compound 649.
1HNMR(300MHz,CDCl 3)6.13-6.11(m,1H),6.09-6.07(m,1H),5.68(s,1H),4.66(bs,1H),4.22-4.15(m,3H),4.12(s,1H),3.67(s,1H),2.62(s,3H),2.60-2.53(m,1H),2.33-2.23(m,2H),1.83(d,3H),1.78-1.69(m,1H),1.44(s,9H),1.07(s,3H),1.06(s,3H),0.98(d,3H),0.96-0.89(m,1H),0.74-0.66(m,1H)。
embodiment 550
ingenol 3-(2-methyl-3-oxo-4-oxaspiro [4.5]-1-in last of the ten Heavenly stems alkene-1-manthanoate) (compound 550)
Compound 550, according to method e preparation, changes as follows: replaced by tetrahydrofuran (THF) methyl alcohol and reaction times is at room temperature 0.5h.
Raw material: compound 650.
1HNMR(300MHz,CDCl 3)6.15-6.13(m,1H),6.09-6.07(m,1H),5.76(s,1H),5.00(d,1H),4.26-4.11(m,4H),3.72(s,1H),2.60-2.55(m,1H),2.45-2.42(m,1H),2.31-2.13(m,5H),1.95-1.90(m,1H),1.82(d,3H),1.78-1.67(m,7H),1.58-1.50(m,2H),1.08(s,3H),1.06(s,3H),1.01(d,3H),0.95-0.89(m,1H),0.75-0.67(m,1H)。
embodiment 551
ingenol 3-(the 1-tertiary butyl-3,5-Dimethyl-pyrazol-4-manthanoate) (compound 551)
Compound 551 is prepared according to method e.
Raw material: compound 651.
1HNMR(300MHz,CDCl 3)6.08-6.05(m,2H),5.58(s,1H),4.47(bs,1H),4.17-4.10(m,4H),3.65(s,1H),2.71(s,3H),2.62-2.57(m,1H),2.36-2.21(m,5H),1.83(d,3H),1.79-1.70(m,1H),1.65(s,9H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.96-0.91(m,1H),0.73-0.65(m,1H)。
embodiment 552
ingenol 3-(3,5-dimethyl isothiazole-4-manthanoate) (compound 552)
Compound 552 is prepared according to method e.
Raw material: compound 652.
embodiment 553
ingenol 3-(the iodo-3-methyl-isothiazol of 5--4-manthanoate) (compound 553)
Compound 553 is prepared according to method e.
Raw material: compound 653.
1HNMR(300MHz,CDCl 3)6.16-6.14(m,1H),6.08(d,1H),5.81(s,1H),4.57(d,1H),4.25-4.12(m,4H),3.75(s,1H),2.74(s,3H),2.73-2.68(m,1H),2.32-2.23(m,2H),1.90(d,3H),1.78-1.69(m,1H),1.07(s,3H),1.06(s,3H),1.00(d,3H),0.96-0.90(m,1H),0.74-0.66(m,1H)。
embodiment 554
ingenol 3-(4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-manthanoate) (compound 554)
Compound 554 is prepared according to method e.
Raw material: compound 654.
1HNMR(300MHz,CDCl 3)7.43(s,1H),7.28-7.23(m,2H),6.90-6.83(m,2H),6.02-6.00(m,1H),5.95-5.93(m,1H),5.73(s,1H),4.22(s,3H),4.16-4.08(m,4H),4.02-3.95(m,2H),3.81(s,3H),3.23(s,1H),1.96-1.87(m,1H),1.75(d,3H),1.58-1.55(m,1H),1.50-1.41(m,1H),1.02(s,3H),1.01(s,3H),0.90-0.83(m,1H),0.69(d,3H),0.63-0.55(m,1H)。
embodiment 555
ingenol 3-(4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-manthanoate) (compound 555)
Compound 555 is prepared according to method e.
Raw material: compound 655.
1HNMR(300MHz,CDCl 3)7.37(s,1H),7.24-7.11(m,4H),6.00-5.98(m,1H),5.87-5.85(m,1H),5.62(s,1H),4.25(s,3H),4.16-4.06(m,2H),3.97-3.88(m,3H),3.00(s,1H),2.36(bs,1H),2.15(s,3H),1.94-1.84(m,1H),1.66(d,3H),1.61-1.48(m,2H),1.04(s,3H),1.02(s,3H),0.90-0.83(m,1H),0.72(d,3H),0.65-0.57(m,1H)。
embodiment 556
ingenol 3-(2-methyl-4-(4-methylsulfonyl phenyl) pyrazoles-3-manthanoate) (compound 556)
Compound 556 is prepared according to method e.
Raw material: compound 656.
1HNMR(300MHz,CDCl 3)7.91(d,2H),7.58(d,2H),7.51(s,1H),6.02-6.01(d,1H),5.96-5.95(m,1H),5.72(s,1H),4.25(s,3H),4.16-4.03(m,5H),3.62(bs,1H),3.07(s,3H),2.14-2.05(m,1H),1.85-1.80(m,1H),1.71(d,3H),1.58-1.49(m,1H),1.33-1.29(m,1H),1.02(s,3H),1.01(s,3H),0.90-0.80(m,1H),0.68(d,3H),0.65-0.57(m,1H)。
embodiment 557
ingenol 3-(2-methyl 4-phenyl-pyrazoles-3-manthanoate) (compound 557)
Compound 557 is prepared according to method e.
Raw material: compound 657.
1HNMR(300MHz,CDCl 3)7.47(s,1H),7.37-7.31(m,5H),6.01(d,1H),5.92-5.91(m,1H),5.71(s,1H),4.24(s,3H),4.16-4.11(m,2H),4.01-3.95(m,3H),3.17(s,1H),2.09-2.03(m,1H),1.93-1.84(m,1H),1.72(d,3H),1.64-1.59(m,1H),1.49-1.41(m,1H),1.03(s,3H),1.02(s,3H),0.88-0.81(m,1H),0.67(d,3H),0.63-0.55(m,1H)。
embodiment 558
ingenol 3-(3,5-dimethyl-1-phenyl-pyrazole-4-manthanoate) (compound 558)
Compound 558 is prepared according to method e.
Raw material: compound 658.
1HNMR(300MHz,CDCl 3)7.53-7.37(m,5H),6.10-6.09(m,1H),6.07-6.05(m,1H),5.67(s,1H),4.70(d,1H),4.22-4.11(m,4H),3.75(s,1H),2.72-2.61(m,2H),2.52(s,3H),2.49(s,3H),2.35-2.25(m,1H),1.86(d,3H),1.80-1.71(m,1H),1.08(s,3H),1.05(s,3H),1.00(d,3H),0.98-0.90(m,1H),0.74-0.66(m,1H)。
embodiment 559
ingenol 3-(1,5-dimethyl-3-phenyl-pyrazole-4-manthanoate) (compound 559)
Compound 559 is prepared according to method e.
Raw material: compound 659.
1HNMR(300MHz,CDCl 3)7.49-7.45(m,2H),7.38-7.33(m,3H),5.98(d,1H),5.89-5.87(m,1H),5.64(s,1H),4.11-4.08(m,2H),3.99-3.94(m,3H),3.85(s,3H),3.21(s,1H),2.60(s,3H),2.46(bs,1H),1.95-1.85(m,1H),1.73(d,3H),1.71-1.64(m,1H),1.50-1.42(m,1H),1.02(s,3H),1.01(s,3H),0.90-0.84(m,1H),0.68(d,3H),0.63-0.55(m,1H)。
embodiment 560
ingenol 3-(1-benzyl-3,5-Dimethyl-pyrazol-4-manthanoate) (compound 560)
Compound 560 is prepared according to method e.
Raw material: compound 660.
1HNMR(300MHz,CDCl 3)7.37-7.28(m,3H),7.16-7.13(m,2H),6.08-6.05(m,2H),5.61(s,1H),5.25(s,2H),4.52(bs,1H),4.18-4.10(m,4H),3.67(s,1H),2.61-2.56(m,1H),2.45(s,3H),2.44-2.41(s,4H),2.31-2.22(m,1H),1.82(d,3H),1.79-1.70(m,1H),1.07(s,3H),1.05(s,3H),0.98(d,3H),0.94-0.86(m,1H),0.73-0.65(m,1H)。
embodiment 561
ingenol 3-(3,5-dimethyl-1-(tetrahydropyran-4-base methyl) pyrazoles-4-manthanoate) (compound 561)
Compound 561 is prepared according to method e.
Raw material: compound 661.
1HNMR(300MHz,CDCl 3)6.08-6.05(m,2H),5.60(s,1H),4.53(bs,1H),4.17-4-11(m,4H),4.00-3.95(m,2H),3.87(d,2H),3.67(s,1H),3.40-3.32(m,2H),2.62-2.57(m,1H),2.51(s,3H),2.39(s,3H),2.32-2.13(m,2H),1.84(d,3H),1.79-1.70(m,1H),1.55-1.35(m,5H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.95-0.85(m,1H),0.73-0.66(m,1H)。
embodiment 562
ingenol 3-(4-methyl-2-oxo-3H-thiazole-5-manthanoate) (compound 562)
Compound 562 is prepared according to method e.
Raw material: compound 662.
1HNMR(300MHz,DMSO-d 6)11.91(bs,1H),5.93(m,1H),5.88-5.86(m,1H),5.73(s,1H),5.41(d,1H),5.12(s,1H),4.64(t,1H),4.18(m,1H),3.98-3.85(m,2H),3.63-3.58(m,1H),2.56-2.51(m,1H),2.38(s,3H),2.33-2.26(m,1H),1.78-1.64(m,4H),1.03(s,6H),0.89(d,3H),0.81-0.74(m,1H),0.65-0.57(m,1H)。
embodiment 563
ingenol 3-(2-methyl-4,5,6,7-tetrahydrochysene indazole-3-manthanoate) (compound 563)
Compound 563 is prepared according to method e.
Raw material: compound 663.
1HNMR(300MHz,CDCl 3)6.12-6.10(m,1H),6.08-6.06(m,1H),5.72(s,1H),4.71(s,1H),4.23-4.11(m,7H),3.71(s,1H),2.71-2.57(m,6H),2.34-2.24(m,1H),1.84(d,3H),1.81-1.70(m,5H),1.07(s,3H),1.05(s,3H),1.00(d,3H),0.96-0.88(m,1H),0.74-0.66(m,1H)。
embodiment 564
ingenol 3-(1,2-dimethyl indole-3-manthanoate) (compound 564)
Compound 564 is prepared according to method e.
Raw material: compound 664.
1HNMR(300MHz,CDCl 3)8.04-8.01(m,1H),7.33-7-19(m,3H),6.13-6.11(m,1H),6.07-6.05(m,1H),5.72(s,1H),4.62(d,1H),4.19-4.13(m,4H),3.81(s,1H),3.68(s,3H),2.76-2.65(m,5H),2.29-2.20(m,1H),1.89(d,3H),1.76-1.67(m,1H),1.05-1.03(m,9H),0.99-0.91(m,1H),0.72-0.64(m,1H)。
embodiment 565
ingenol 3-(5-methoxyl group-1,2-dimethyl-indol-3-manthanoate) (compound 565)
Compound 565 is prepared according to method e.
Raw material: compound 665.
1HNMR(300MHz,CDCl 3)7.56(d,1H),7.19(d,1H),6.88(dd,1H),6.13-6.11(m,1H),6.07-6.06(m,1H),5.69(s,1H),4.66(d,1H),4.18-4.13(m,4H),3.83(s,1H),3.82(s,3H),3.65(s,3H),2.73(s,3H),2.72-2.62(m,2H),2.29-2.20(m,1H),1.90(d,3H),1.76-1.69(m,1H),1.05(s,3H),1.03(s,3H),1.02(d,3H),0.99-0.92(m,1H),0.72-0.64(m,1H)。
embodiment 566
ingenol 3-(1,3,5-trimethylpyrazol-4-manthanoate) (compound 566)
Compound 566 is prepared according to method e.
Raw material: compound 630.
1HNMR(300MHz,CDCl 3)6.08-6.05(m,2H),5.62(s,1H),6.07(d,1H),4.19-4.10(m,4H),3.73(s,3H),3.71(s,1H),3.73(t,1H),2.62-2.57(m,1H),2.50(s,3H),2.38(s,3H),2.32-2.22(m,1H),1.83(d,3H),1.78-1.69(m,1H),1.06(s,3H),1.05(s,3H),0.99(d,3H),0.97-0.90(m,1H),0.73-0.65(m,1H)。
embodiment 567
ingenol 3-(4-methyl isophthalic acid, 2,5- diazole-3-manthanoate) (compound 567)
Compound 567 is prepared according to method e.
Raw material: compound 667.
1HNMR(300MHz,CDCl 3)6.18-6.17(m,1H),6.09-6.07(m,1H),5.88(s,1H),4.67(d,1H),4.23-4.10(m,4H),3.71(s,1H),2.66-2.60(m,4H),2.31-2.21(m,2H),1.86(d,3H),1.84-1.74(m,1H),1.07(s,3H),1.04(s,3H),1.02(d,3H),0.96-0.89(m,1H),0.75-0.67(m,1H)。
embodiment 568
ingenol 3-(2-methoxyl group-4-methyl-thiazole-5-manthanoate) (compound 568)
Compound 568 is prepared according to method e.
Raw material: compound 668.
1HNMR(300MHz,CDCl 3)6.08-6.05(m,2H),5.65(s,1H),4.53(bs,1H),4.22-4.13(m,3H),4.06(s,1H),3.58(s,1H),3.33(s,3H),2.60(s,3H),2.59-2.52(m,1H),2.41(bs,1H),2.31-2.22(m,1H),1.81(d,3H),1.78-1.73(m,1H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.96-0.89(m,1H),0.74-0.67(m,1H)。
embodiment 569
(4,5-dimethyl is different for ingenol 3- azoles-3-manthanoate) (compound 569)
Compound 569 is prepared according to method e.
Raw material: compound 669.
1HNMR(300MHz,CDCl 3)6.11-6.10(m,1H),6.06-6.04(m,1H),5.84(s,1H),4.34(d,1H),4.23-4.13(m,3H),4.05(d,1H),3.89(s,1H),2.65-2.59(m,2H),2.39(s,3H),2.30-2.21(m,1H),2.14(s,3H),1.85(d,3H),1.82-1.73(m,1H),1.07(s,3H),1.05(s,3H),1.00(d,3H),0.96-0.88(m,1H),0.74-0.66(m,1H)。
embodiment 570
ingenol 3-(the bromo-1-methyl pyrazole of 4--3-manthanoate) (compound 570)
Compound 570 is prepared according to method e.
Raw material: compound 670.
1HNMR(300MHz,CDCl 3)7.50(s,1H),6.11-6.09(m,1H),6.08-6.06(m,1H),5.81(s,1H),4.18-4.11(m,3H),4.04(d,1H),3.98(s,3H),3.88(s,1H),3.75(d,1H),2.73-2.68(m,1H),2.30-2.21(m,2H),1.88(d,3H),1.82-1.73(m,1H),1.09(s,3H),1.06(s,3H),1.01(d,3H),0.99-0.92(m,1H),0.75-0.67(m,1H)。
embodiment 571
ingenol 3-(1,3-dimethyl indole-2-manthanoate) (compound 571)
Compound 571 is prepared according to method e.
Raw material: compound 671.
1HNMR(300MHz,CDCl 3)7.68-7.65(m,1H),7.40-7.32(m,2H),7.17-7.12(m,1H),6.14-6.13(m,1H),6.08-6.06(m,1H),5.79(s,1H),4.60(bs,1H),4.23-4.13(m,4H),4.01(s,3H),3.76(s,1H),2.69-2.64(m,1H),2.59(s,3H),2.54-2.49(m,1H),2.32-2.23(m,1H),1.88(d,3H),1.78-1.67(m,1H),1.06(s,3H),1.05(s,3H),1.02(d,3H),0.97-0.88(m,1H),0.73-0.65(m,1H)。
embodiment 572
ingenol 3-(5-methoxyl group-1,3-dimethyl-indol-2-manthanoate) (compound 572)
Compound 572 is prepared according to method e.
Raw material: compound 672.
1HNMR(300MHz,CDCl 3)7.26-7.23(m,1H),7.06-7.00(m,2H),6.14-6.12(m,1H),6.08-6.06(m,1H),5.78(s,1H),4.58(bs,1H),4.22-4.14(m,4H),3.99(s,3H),3.87(s,3H),3.75(s,1H),2.68-2.62(m,1H),2.55(s,3H),2.49(bs,1H),2.33-2.23(m,1H),1.88(d,3H),1.78-1.69(m,1H),1.06(s,3H),1.05(s,3H),1.02(d,3H),0.97-0.88(m,1H),0.73-0.65(m,1H)。
embodiment 573
ingenol 3-(2,4-dimethyl-6-oxo-pyrans-3-manthanoate) (compound 573)
Compound 573 is prepared according to method e.
Raw material: compound 673.
1HNMR(300MHz,CDCl 3)6.14-6.13(m,1H),6.10-6.08(m,1H),6.04(s,1H),5.75(s,1H),4.76(bs,1H),4.22-4.18(m,3H),4.12(s,1H),3.76(s,1H),2.51-2.46(m,1H),2.44(s,3H),2.33-2.26(m,1H),2.23(d,3H),2.11(bs,1H),1.82(d,3H),1.79-1.70(m,1H),1.08(s,3H),1.06(s,3H),0.98(d,3H),0.96-0.88(m,1H),0.75-0.67(m,1H)。
embodiment 574
ingenol 3-(1-methyl-3-phenyl-indole-2-manthanoate) (compound 574)
Compound 574 is prepared according to method e.
Raw material: compound 674.
1HNMR(300MHz,CDCl 3)7.46-7.34(m,8H),7.15-7.10(m,1H),6.01-5.99(m,1H),5.89-5.87(m,1H),5.73(s,1H),4.12-4.11(m,5H),3.98-3.91(m,2H),3.81-3.79(d,1H),3.02(s,1H),2.35(bs,1H),1.92-1.83(m,1H),1.70-1.66(d,4H),1.54-1.45(m,1H),1.03(s,3H),1.03(s,3H),0.89-0.82(m,1H),0.74(d,3H),0.64-0.56(m,1H)。
embodiment 575
(3-methyl-5-(trifluoromethyl) is different for ingenol 3- azoles-4-manthanoate) (compound 575)
Compound 575 is prepared according to method e.
Raw material: compound 675.
1HNMR(300MHz,CDCl 3)6.16-6.14(m,1H),6.09-6.06(m,1H),5.77(s,1H),4.25-4.14(m,3H),4.10(s,1H),3.08(bs,3H),2.57-2.48(m,4H),2.31-2.22(m,1H),1.81(d,3H),1.78-1.69(m,1H),1.06(s,6H),0.99(d,3H),0.94-0.87(m,1H),0.74-0.66(m,1H)。
embodiment 576
ingenol 3-(1,3-dimethyl pyrrole-2-manthanoate) (compound 576)
Compound 576, according to method e preparation, changes as follows: replaced by tetrahydrofuran (THF) methyl alcohol and reaction times is at room temperature 0.5h.
Raw material: compound 676.
1HNMR(300MHz,CDCl 3)6.71(d,1H),6.08-6.04(m,2H),5.98(d,1H),5.63(s,1H),4.50(d,1H),4.19-4.09(m,4H),3.87(s,3H),3.72(s,1H),2.64-2.53(m,2H),2.31(s,3H),2.30-2.22(m,1H),1.84(d,3H),1.78-1.71(m,1H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.95-0.86(m,1H),0.73-0.65(m,1H)。
embodiment 577
ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl) pyrazoles-4-manthanoate) (compound 577)
Compound 577 is prepared according to method e.
Raw material: compound 677.
1HNMR(300MHz,CDCl 3)6.09-6.08(m,1H),6.06-6.04(m,1H),5.68(s,1H),4.82(d,1H),4.62(q,2H),4.22-4.12(m,4H),3.77(s,1H),2.97(bs,1H),2.63-2.58(m,1H),2.55(s,3H),2.41(s,3H),2.34-2.24(m,1H),1.83(d,3H),1.79-1.70(m,1H),1.07(s,3H),1.05(s,3H),0.99(d,3H),0.96-0.88(m,1H),0.73-0.65(m,1H)。
embodiment 578
ingenol 3-(1-cyclopropyl-2,5-Dimethyl-pyrrol-3-manthanoate) (compound 578)
Compound 578 is prepared according to method e.
Raw material: compound 678.
1HNMR(300MHz,CDCl 3)6.18-6.17(m,1H),6.04-6.00(m,2H),5.58(s,1H),4.42(d,1H),4.16-4.05(m,4H),3.60(s,1H),2.93-2.87(m,1H),2.76(bs,1H),2.61-2.56(m,4H),2.28-2.19(m,4H),1.80(d,3H),1.78-1.71(m,1H),1.15-1.08(m,2H),1.06(s,3H),1.03(s,3H),0.99(d,3H),0.95-0.88(m,3H),0.72-0.65(m,1H)。
embodiment 579
ingenol 3-(1,2,5-trimethylammonium pyrroles-3-manthanoate) (compound 579)
Compound 579 is prepared according to method e.
Raw material: compound 679.
1HNMR(300MHz,CDCl 3)6.23-6.22(m,1H),6.05-6.00(m,2H),5.57(s,1H),4.31(d,1H),4.16-4.06(m,4H),3.57(s,1H),3.41(s,3H),2.60-2.54(m,2H),2.51(s,3H),2.28-2.19(m,4H),1.81(d,3H),1.79-1.72(m,1H),1.07(s,3H),1.04(s,3H),1.00(d,3H),0.98-0.92(m,1H),0.73-0.65(m,1H)。
embodiment 580
ingenol 3-(2,4-dimethyl-1H-pyrroles-3-manthanoate) (compound 580)
Compound 580 is prepared according to method e.
Raw material: compound 680.
1HNMR(300MHz,CDCl 3)10.51(bs,1H),6.09-6.05(m,2H),5.95(d,1H),5.83(s,1H),4.89(bs,1H),4.54(s,1H),4.23-4.07(m,4H),3.11(bs,1H),2.59-2.54(m,1H),2.38(s,3H),2.35-2.25(m,4H),1.82(d,3H),1.79-1.74(m,1H),1.09(s,3H),1.06(s,3H),0.98-0.88(m,4H),0.75-0.67(m,1H)。
embodiment 581
ingenol 3-(1-methylpyrrole-2-manthanoate) (compound 581)
Compound 581 is prepared according to method e.
Raw material: compound 681.
1HNMR(300MHz,CDCl 3)6.96(dd,1H),6.84(t,1H),6.14(dd,1H),6.06-6.03(m,2H),5.69(s,1H),4.43(d,1H),4.18-4.06(m,4H),3.93(s,3H),3.64(s,1H),2.77(bs,1H),2.62-2.57(m,1H),2.31-2.21(m,1H),1.82(d,3H),1.80-1.73(m,1H),1.07(s,3H),1.05(s,3H),1.01(d,3H),0.97-0.91(m,1H),0.74-0.66(m,1H)。
embodiment 582
ingenol 3-(4-methyl isophthalic acid H-pyrroles-2-manthanoate) (compound 582)
Compound 582 is prepared according to method e.
Raw material: compound 682.
1HNMR(300MHz,CDCl 3)9.54(s,1H),6.77-6.72(m,2H),6.06-6.02(m,2H),5.69(s,1H),4.80(d,1H),4.26-4.07(m,4H),3.80(s,1H),2.79(t,1H),2.62-2.56(m,1H),2.32-2.23(m,1H),2.11(s,3H),1.82-1.73(m,4H),1.05(s,3H),1.04(s,3H),1.01(d,3H),0.96-0.88(m,1H),0.73-0.66(m,1H)。
embodiment 583
ingenol 3-(1,5-dimethyl pyrrole-2-manthanoate) (compound 583)
Compound 583 is prepared according to method e.
Raw material: compound 683.
1HNMR(300MHz,CDCl 3)6.91(d,1H),6.04-6.02(m,2H),5.94(d,1H),5.67(s,1H),4.39(d,1H),4.17-4.05(m,4H),3.83(s,3H),3.64(s,1H),2.80(t,1H),2.61-2.56(m,1H),2.30-2.21(m,4H),1.81(d,3H),1.79-1.72(m,1H),1.07(s,3H),1.04(s,3H),1.01(d,3H),0.97-0.91(m,1H),0.73-0.65(m,1H)。
embodiment 584
ingenol 3-(3-methyl isophthalic acid H-pyrroles-2-manthanoate) (compound 584)
Compound 584 is prepared according to method e.
Raw material: compound 684.
1HNMR(300MHz,CDCl 3)9.33(s,1H),6.87(t,1H),6.11(t,1H),6.08-6.04(m,2H),5.66(s,1H),4.76(d,1H),4.23-4.10(m,4H),3.81(s,1H),2.62-2.57(m,2H),2.34-2.23(m,4H),1.81(d,3H),1.79-1.70(m,1H),1.05(s,3H),1.04(s,3H),1.00(d,3H),0.96-0.88(m,1H),0.73-0.65(m,1H)。
embodiment 585
ingenol 3-(1-cyclopropyl pyrroles-2-manthanoate) (compound 585)
Compound 585 is prepared according to method e.
Raw material: compound 685.
1HNMR(300MHz,CDCl 3)6.95(dd,1H),6.91(t,1H),6.09(dd,1H),6.05-6.03(m,2H),5.70(s,1H),4.40(d,1H),4.18-4.07(m,4H),3.73(m,1H),3.64(s,1H),2.74(t,1H),2.62-2.57(m,1H),2.31-2.21(m,1H),1.83(d,3H),1.81-1.72(m,1H),1.07(s,3H),1.05(s,3H),1.03-0.91(m,8H),0.73-0.66(m,1H)。
embodiment 586
ingenol 3-(1-ethyl-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 586)
Compound 586 is prepared according to method e.
Raw material: compound 686.
1HNMR(300MHz,CDCl 3)6.34-6.33(m,1H),6.05-6.02(m,2H),5.58(s,1H),4.60(d,1H),4.17-4.08(m,4H),3.81(q,2H),3.73(s,1H),2.77(bs,1H),2.64-2.59(m,1H),2.48(s,3H),2.30-2.21(m,1H),2.19(d,3H),1.83(d,3H),1.77-1.68(m,1H),1.33(t,3H),1.06(s,3H),1.04(s,3H),0.98(d,3H),0.97-0.91(m,1H),0.72-0.64(m,1H)。
embodiment 587
ingenol 3-(1-allyl group-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 587)
Compound 587 is prepared according to method e.
Raw material: compound 687.
1HNMR(300MHz,CDCl 3)6.32(q,1H),6.05-6.03(m,2H),5.94-5.81(m,1H),5.60(s,1H),5.23-5.18(m,1H),5.03-4.96(m,1H),4.62(d,1H),4.39-4.36(m,2H),4.17-4.08(m,4H),3.74(s,1H),2.81(bs,1H),2.64-2.59(m,1H),2.45(s,3H),2.31-2.22(m,1H),2.19(d,3H),1.83(d,3H),1.77-1.68(m,1H),1.07(s,3H),1.04(s,3H),0.98(d,3H),0.97-0.90(m,1H),0.72-0.64(m,1H)。
embodiment 588
ingenol 3-(1-(Cvclopropvlmethvl)-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 588)
Compound 588 is prepared according to method e.
Raw material: compound 688.
1HNMR(300MHz,CDCl 3)6.42(q,1H),6.05-6.03(m,2H),5.58(s,1H),4.58(d,1H),4.17-4.08(m,4H),3.73(s,1H),3.63(d,2H),2.74(s,1H),2.64-2.59(m,1H),2.50(s,3H),2.30-2.24(m,1H),2.20(d,3H),1.83(d,3H),1.77-1.68(m,1H),1.13-1.08(m,1H),1.07(s,3H),1.04(s,3H),0.98(d,3H),0.97-0.91(m,1H),0.72-0.59(m,3H),0.34-0.29(m,2H)。
embodiment 589
ingenol 3-(1-(2-methoxy ethyl)-2,4-Dimethyl-pyrrol-3-manthanoate) (compound 589)
Compound 589 is prepared according to method e.
Raw material: compound 689.
1HNMR(300MHz,CDCl 3)6.37(s,1H),6.05-6.03(m,2H),5.57(s,1H),4.54(d,1H),4.16-4.08(m,4H),3.94(t,2H),3.71(s,1H),3.58(t,2H),3.33(s,3H),2.70-2.58(m,2H),2.49(s,3H),2.30-2.21(m,1H),2.19(s,3H),1.83(d,3H),1.77-1.68(m,1H),1.07(s,3H),1.04(s,3H),0.98(d,3H),0.97-0.91(m,1H),0.72-0.64(m,1H)。
embodiment 701:
ingenol 3-(N-Ethyl-carbamic acid ester) (compound 701)
Compound 701 is prepared according to method e.
Raw material: compound 801.
1hNMR (300MHz, DMSO-d 6) δ 6.98 (t, 1H), 5.86-5.83 (m, 2H), 5.37 (s, 1H), 5.20 (bs, 1H), 4.85 (s, 1H), 4.19-4.15 (m, 1H), 3.95-3.84 (m, 2H), 3.57-3.5 (m, 2H) (absorb with water and overlap), 3.05-3.00 (m, 2H), 2.5 (m, 1H) (overlap with solvent absorbing), 2.31-2.23 (m, 1H), 1.71 (d, 3H), 1.68-1.63 (m, 1H), 1.05 (s, 3H), 1.03 (t, 3H), 1.03 (s, 3H), 0.87 (d, 3H), 0.84-0.74 (m, 1H), 0.65-0.57 (m, 1H).
embodiment 702:
ingenol 3-(N, N-dimethyl-amino manthanoate) (compound 702)
Compound 702 is prepared according to method e.
Raw material: compound 802.
1hNMR (300MHz, DMSO-d 6) δ 5.86-5.84 (m, 2H), 5.45 (s, 1H), 5.28 (d, 1H), 4.94 (s, 1H), 4.65 (t, 1H), 4.20-4.15 (m, 1H), 3.97-3.84 (m, 2H), 3.57-3.55 (m, 1H), 2.84 (s, 6H), 2.5 (m, 1H) (overlapping with solvent absorbing), 2.33-2.24 (m, 1H), 1.70 (d, 3H), 1.68-1.63 (m, 1H), 1.05 (s, 3H), 1.03 (s, 3H), 0.88 (d, 3H), 0.81-0.74 (m, 1H), 0.64-0.57 (m, 1H).
embodiment 703:
ingenol 3-(morpholine-4-manthanoate) (compound 703)
Compound 703 is prepared according to method e.
Raw material: compound 803.
1HNMR(300MHz,DMSO-d 6)δ5.86-5.85(m,2H),5.51(s,1H),5.29(d,1H),5.05(s,1H),4.62(t,1H),4.17(m,1H),3.97-3.83(m,2H),3.60-3.53(m,5H),3.40-3.32(m,4H),2.45-2.40(m,1H),2.32-2.23(m,1H),1.70(d,3H),1.68-1.63(m,1H),1.05(s,3H),1.03(s,3H),0.87(d,3H),0.81-0.74(m,1H),0.64-0.56(m,1H)。
embodiment 704:
ingenol 3-(tetramethyleneimine-1-manthanoate) (compound 704)
Compound 704 is prepared according to method e.
Raw material: compound 804.
1hNMR (300MHz, DMSO-d 6) δ 5.86-5.83 (m, 2H), 5.45 (s, 1H), 5.24 (d, 1H), 4.95 (s, 1H), 4.60 (t, 1H), 4.19-4.15 (m, 1H), 3.99-3.84 (m, 2H), 3.56 (d, 1H), 3.43-3.39 (m, 1H), 3.30-3.18 (m, 3H), 2.5 (m, 1H) (overlap with solvent absorbing), 2.32-2.24 (m, 1H), 1.84-1.76 (m, 4H), 1.72-1.65 (m, 4H), 1.05 (s, 3H), 1.03 (s, 3H), 0.87 (d, 3H), 0.83-0.74 (m, 1H), 0.64-0.56 (m, 1H).
embodiment 705:
ingenol 3-(N-Methyl-N-phenyl-carbamate) (compound 705)
Compound 705 is prepared according to method e.Obtaining compound 705, is amorphous compound.
Raw material: compound 805.
1HNMR(300MHz,DMSO-d 6)δ7.37-7.30(m,4H),7.22-7.16(m,1H),5.85-5.84(m,1H),5.77(s,1H),5.54(s,1H),5.34(d,1H),4.97(s,1H),4.61(t,1H),4.16-4.11(m,1H),3.97-3.82(m,2H),3.57(d,1H),3.24(s,3H),2.24-2.16(m,1H),2.09-1.95(m,1H),1.68(d,3H),1.53-1.45(m,1H),1.03(s,3H),1.02(s,3H),0.76-0.70(m,1H),0.65(d,3H),0.58-0.50(m,1H)。
embodiment 706:
ingenol 3-(N, N-Diethyl-carbamic acid ester) (compound 706)
Compound 706 is prepared according to method e.
Raw material: compound 806.
1hNMR (300MHz, DMSO-d 6) δ 5.87-5.84 (m, 2H), 5.49 (s, 1H), 5.27 (d, 1H), 4.94 (s, 1H), 4.60 (t, 1H), 4.21-4.16 (m, 1H), 3.97-3.83 (m, 2H), 3.58 (d, 1H), 3.38-3.10 (m, 4H), 2.5 (m, 1H) (overlapping with solvent absorbing), 2.34-2.25 (m, 1H), 1.70 (d, 3H), 1.69-1.62 (m, 1H), 1.05 (t, 6H), 1.05 (s, 3H), 1.03 (s, 3H), 0.88 (d, 3H), 0.88-0.74 (m, 1H), 0.64-0.56 (m, 1H).
embodiment 707:
ingenol 3-(piperidines-1-manthanoate) (compound 707)
Compound 707 is prepared according to method e.
Raw material: compound 807.
1HNMR(300MHz,DMSO-d 6)δ5.86-5.84(m,2H),5.47(s,1H),5.29(d,1H),4.90(s,1H),4.61(t,1H),4.20-4.15(m,1H),3.96-3.83(m,2H),3.57(d,1H),3.38-3.27(m,4H),2.48-2.42(m,1H),2.33-2.24(m,1H),1.70(d,3H),1.68-1.62(m,1H),1.58-1.40(m,6H),1.05(s,3H),1.03(s,3H),0.88(d,3H),0.84-0.75(m,1H),0.64-0.56(m,1H)。
embodiment 708:
ingenol 3-(N-Benzyl-N-methyl-carbamate) (compound 708)
Compound 708 is prepared according to method e.
Raw material: compound 808.
1HNMR(300MHz,DMSO-d 6)δ7.31-7.24(m,5H),5.86-5.82(m,2H),5.53(s,1H),5.34-5.28(m,1H),5.03(s,0.4H),4.91(s,0.6H),4.61(t,1H),4.54-4.32(m,2H),4.24-4.12(m,1H),3.99-3.83(m,2H),3.58(d,1H),2.84(s,3H),2.37-2.18(m,2H),1.73-1.47(m,4H),1.05(s,3H),1.02(s,3H),0.90-0.70(m,4H),0.61-0.53(m,1H)。
embodiment 709:
ingenol 3-(N-cyclohexyl-N-methyl-carbamate) (compound 709)
Compound 709 is prepared according to method e.
Raw material: compound 809.
1hNMR (300MHz, DMSO-d 6) δ 5.86-5.85 (m, 2H), 5.50 (s, 1H), 5.27-5.25 (m, 1H), 4.96-4.92 (m, 1H), 4.61 (t, 1H), 4.21-4.16 (m, 1H), 3.97-3.75 (m, 3H), 3.58 (d, 1H), 2.72 (s, 3H), 2.5 (m, 1H) (overlapping with solvent absorbing), 2.36-2.26 (m, 1H), 1.78-1.09 (m, 14H), 1.04 (s, 3H), 1.03 (s, 3H), 0.88 (d, 3H), 0.84-0.74 (m, 1H), 0.65-0.57 (m, 1H).
embodiment 710:
ingenol 3-(N-cyclohexyl-carbamate) (compound 710)
Compound 710 is prepared according to method e.
Raw material: compound 810.
1hNMR (300MHz, DMSO-d 6) δ 6.90 (d, 1H), 5.85-5.81 (m, 2H), 5.35 (s, 1H), 5.16 (d, 1H), 4.84 (m, 1H), 4.58 (t, 1H), 4.20-4.15 (m, 1H), 3.97-3.81 (m, 2H), 3.50 (d, 1H), 3.25-3.20 (m, 1H), 2.5 (m, 1H) (overlap with solvent absorbing), 2.32-2.23 (m, 1H), 1.80-1.52 (m, 10H), 1.30-1.09 (m, 4H), 1.06 (s, 3H), 1.04 (s, 3H), 0.87 (d, 3H), 0.81-0.74 (m, 1H), 0.65-0.57 (m, 1H).
embodiment 711:
ingenol 3-(N-phenyl-carbamate) (compound 711)
Compound 711 is prepared according to method e.
Raw material: compound 811.
1HNMR(300MHz,DMSO-d 6)δ9.44(s,1H),7.50(d,2H),7.29(t,2H),6.99(t,1H),5.91-5.87(m,2H),5.55(s,1H),5.31(d,1H),4.99(s,1H),4.62(t,1H),4.23-4.18(m,1H),3.99-3.84(m,2H),3.60(d,1H),2.60-2.57(m,1H),2.36-2.27(m,1H),1.76(d,3H),1.74-1.66(m,1H),1.05(s,3H),1.04(s,3H),0.91(d,3H),0.82-0.75(m,1H),0.67-0.59(m,1H)。
embodiment 712:
ingenol 3-(N-(indane-1-base)-carbamate) (compound 712)
Compound 712 is prepared according to method e.
Raw material: compound 812.
1HNMR(300MHz,DMSO-d 6)δ7.43(d,1H),7.26-7.18(m,4H),5.86-5.84(m,2H),5.46(s,1H),5.20(d,1H),5.01(q,1H),4.87(s,1H),4.59(t,1H),4.21-4.15(m,1H),3.99-3.83(m,2H),3.54(d,1H),2.98-2.89(m,1H),2.84-2.73(m,1H),2.47-2.35(m,2H),2.31-2.22(m,1H),1.91-1.79(m,1H),1.78-1.62(m,4H),1.05(s,3H),1.03(s,3H),0.86(d,3H),0.81-0.74(m,1H),0.64-0.57(m,1H)。
embodiment 713:
ingenol 3-(3,3-DimethYI-pineridin-1-manthanoate) (compound 713)
Compound 713 is prepared according to method e.
Raw material: compound 813.
1HNMR(300MHz,CDCl 3)δ6.04-6.02(m,1H),5.99(s,1H),5.19-5.17(m,1H),4.78-4.69(m,1H),4.16-4.07(m,3H),4.01(bs,1H),3.85-3.77(m,1H),3.49-3.05(m,4H),2.66(bs,1H),2.51(m,1H),2.29-2.22(m,1H),1.78(m,3H),1.70-1.55(m,3H),1.42-1.31(m,2H),1.10(s,3H),1.04(s,3H),0.99-0.82(m,10H),0.72-0.65(m,1H)。
embodiment 714:
ingenol 3-(N-methyl-N-naphthane-1-base-carbamate) (compound 714)
Compound 714 is prepared according to method e.
Raw material: compound 814.
1HNMR(300MHz,CDCl 3)δ7.19-7.10(m,4H),6.06-5.95(m,2H),5.50-5.20(m,2H),4.74-4.50(2bs,1H),4.18-3.55(m,5H),2.77-1.59(m,16H),1.16-1.05(m,6H),0.97-0.82(m,4H),0.72-0.63(m,1H)。
embodiment 715:
ingenol 3-(N-(2-cyano group-1-methyl-ethyl)-N-Methyl-carbamic acid ester) (compound 715)
Compound 715 is prepared according to method e.
Raw material: compound 815.
1HNMR(300MHz,CDCl 3)δ6.05-6.01(m,2H),5.26(s,1H),4.84-4.38(m,2H),4.15-4.09(m,3H),4.03(m,1H),3.89-3.70(m,1H),2.91-2.83(m,3H),2.64-2.42(m,3H),2.31-2.23(m,1H),1.85-1.71(m,4H),1.60(m,2H),1.40-1.35(m,2H),1.11-1.10(m,3H),1.05(s,3H),0.98-0.98(m,4H),0.73-0.65(m,1H)。
embodiment 716:
ingenol 3-(N-methyl-N-((S)-1-styroyl)-carbamate) (compound 716)
Compound 716 is prepared according to method e.
Raw material: compound 816.
1HNMR(300MHz,CDCl 3)δ7.35-7.27(m,5H),6.05-6.04(m,1H),6.00(s,1H),5.57-5.40(m,1H),5.29(s,1H),4.73-4.45(2bs,1H),4.13-4.08(m,3H),4.03(s,1H),3.76-3.69(2bs,1H),2.73-2.17(m,6H),1.81(d,3H),1.80-1.54(m,4H),1.11(s,3H),1.05(s,3H),0.95-0.84(m,4H),0.70-0.62(m,1H)。
embodiment 717:
ingenol 3-(N-methyl-N-(Cvclopropvlmethvl)-carbamate) (compound 717)
Compound 717 is prepared according to method e.
Raw material: compound 817.
1HNMR(300MHz,CDCl 3)δ6.04-6.03(d,1H),5.99(s,1H),5.20-5.17(m,1H),4.73(bs,1H),4.16-4.06(m,3H),4.02(m,1H),3.83-3.77(m,1H),3.29-3.10(m,2H),3.00(s,3H),2.63(bs,1H),2.54-2.50(m,1H),2.30-2.21(m,1H),1.80-1.70(m,4H),1.10(s,3H),1.05(s,3H),0.99-0.88(m,5H),0.73-0.65(m,1H),0.56-0.50(m,2H),0.26-0.19(m,2H)。
embodiment 718:
ingenol 3-(N-(the fluoro-phenyl of 3-)-N-Methyl-carbamic acid ester) (compound 718)
Compound 718 is prepared according to method e.Obtaining compound 718, is amorphous compound.
Raw material: compound 818.
1HNMR(300MHz,CDCl 3)δ7.36-7.28(m,1H),7.09-7.02(m,2H),6.99-6.93(m,1H),6.00(d,1H),5.94(s,1H),5.35(s,1H),4.38(bs,1H),4.13-4.05(m,3H),3.99(d,1H),3.59(s,1H),3.32(s,3H),2.45(t,1H),2.19-2.12(m,2H),1.76(d,3H),1.70-1.62(m,1H),1.09(s,3H),1.05(s,3H),0.94-0.88(m,1H),0.79(d,3H),0.70-0.62(m,1H)。
embodiment 719:
ingenol 3-(N-(2,5-dimethyl pyrazole-3-base)-N-Methyl-carbamic acid ester) (compound 719)
Compound 719 is prepared according to method e.
Raw material: compound 819.
1HNMR(300MHz,CDCl 3)δ6.02(bd,1H),5.95(bs,1H),5.88(s,1H),5.40(s,1H),4.20-4.04(m,4H),3.96(m,1H),3.62(s,3H),3.41(bs,1H),3.21(s,3H),2.51(bs,1H),2.22(s,3H),2.09-2.00(m,1H),1.80-1.60(m,5H),1.07(s,3H),1.05(s,3H),0.92-0.86(m,1H),0.77(bd,3H),0.69-0.64(m,1H)。
embodiment 720:
((3,5-dimethyl is different for N-for ingenol 3- azoles-4-base)-N-Methyl-carbamic acid ester) (compound 720)
Compound 720 is prepared according to method e.
Raw material: compound 820.
1HNMR(300MHz,CDCl 3)δ6.05-6.02(m,2H),5.28(s,1H),4.79(bs,1H),4.37-4.24(m,2H),4.14-4.10(m,3H),4.04(bs,1H),3.83(bs,1H),2.80(s,4H),2.49(bs,1H),2.38(s,3H),2.31-2.22(m,4H),1.83-1.69(m,4H),1.09(s,3H),1.05(s,3H),0.97-0.90(m,4H),0.72-0.65(m,1H)。
embodiment 721:
ingenol 3-(N-(1,5-dimethyl pyrazole-3-base)-N-Methyl-carbamic acid ester) (compound 721)
Compound 721 is prepared according to method e.
Raw material: compound 821.
1HNMR(300MHz,CDCl 3)δ6.20-5.87(m,4H),5.53(s,1H),4.17-4.11(m,3H),3.89(d,1H),3.69(s,3H),3.50(bs,1H),3.28(s,3H),2.51(bs,1H),2.30-2.21(m,5H),1.85(d,3H),1.72-1.63(m,1H),1.13(s,3H),1.06(s,3H),1.00-0.93(m,1H),0.85(d,3H),0.72-0.65(m,1H)。
embodiment 722:
ingenol 3-(N-cyclopentyl-N-Methyl-carbamic acid ester) (compound 722)
Compound 722 is prepared according to method e.
Raw material: compound 822.
1HNMR(300MHz,CDCl 3)δ6.05-6.03(m,1H),5.99-5.98(bs,1H),5.16(2xs,1H),4.70(bs,1H),4.17-4.02(m,4H),3.77(s,1H),3.32-3.27(m,1H),2.81(s,3H),2.53-2.50(m,2H),2.29-2.19(m,1H),1.85-1.70(m,8H),1.33-1.13(m,4H),1.11(s,3H),1.05(s,3H),0.97-0.88(m,4H),0.73-0.65(m,1H)。
embodiment 723:
ingenol 3-(N-cyclopropyl-N-Methyl-carbamic acid ester) (compound 723)
Compound 723 is prepared according to method e.
Raw material: compound 823.
1HNMR(300MHz,CDCl 3)δ6.05-6.03(m,1H),6.00-5.98(m,1H),5.15(s,1H),4.46(bs,1H),4.16-4.02(m,4H),3.72(s,1H),3.36-3.28(m,3H),2.92(s,1H),2.60-2.50(m,2H),2.29-2.20(m,1H),1.81(d,3H),1.80-1.71(m,1H),1.11(s,3H),1.05(s,3H),0.97-0.90(m,4H),0.77-0.65(m,5H)。
embodiment 724:
ingenol 3-(N-methyl-N-(2-pyridyl)-carbamate) (compound 724)
Compound 724 is prepared according to method e.
Raw material: compound 824.
1HNMR(300MHz,CDCl 3)δ8.36-8.34(m,1H),7.81-7.75(m,1H),7.29(d,1H),7.15-7.11(m,1H),6.34(bs,1H),6.04-6.02(m,1H),5.98-5.96(m,1H),5.77(s,1H),4.19-4.13(m,3H),3.90(d,1H),3.61(d,1H),3.44(s,3H),2.49(t,1H),2.34-2.25(m,1H),2.09-2.04(m,1H),1.81(d,3H),1.72-1.64(m,1H),1.18(s,3H),1.08(s,3H),0.99-0.93(m,1H),0.78(d,3H),0.72-0.64(m,1H)。
embodiment 725:
ingenol 3-(4-oxo-2,3-dihydroquinoline-1-manthanoate) (compound 725)
Compound 725 is prepared according to method e.
Raw material: compound 825.
1HNMR(300MHz,CDCl 3)δ8.02-7.99(m,1H),7.81(d,1H),7.53-7.48(m,1H),7.24-7.19(m,1H),6.06(d,1H),6.00(d,1H),5.53(s,1H),4.89(d,1H),4.36-4.27(m,1H),4.18-4.05(m,5H),3.83(s,1H),2.85-2.75(m,3H),2.40-2.35(m,1H),2.30-2.20(m,1H),1.84(d,3H),1.72-1.63(m,1H),1.06(s,3H),1.04(s,3H),0.93-0.86(m,4H),0.71-0.63(m,1H)。
embodiment 726:
ingenol 3-(3,4-dihydro-2H-quinoline-1-manthanoate) (compound 726)
Compound 726 is prepared according to method e.
Raw material: compound 826.
1HNMR(300MHz,CDCl 3)δ7.68(bd,1H),7.17-7.00(m,3H),6.03-6.01(m,1H),5.98(d,1H),5.43(s,1H),4.64(bs,1H),4.14-4.09(m,3H),4.03(d,1H),3.84-3.72(m,3H),2.80(t,2H),2.67(bs,1H),2.43(bs,1H),2.25-2.19(m,1H),2.02-1.93(m,2H),1.83(d,3H),1.74-1.65(m,1H),1.08(s,3H),1.04(s,3H),0.93-0.86(m,4H),0.71-0.63(m,1H)。
embodiment 727:
ingenol 3-(indoline-1-manthanoate) (compound 727)
Compound 727 is prepared according to method e.
Raw material: compound 827.
1HNMR(300MHz,CDCl 3)δ7.87(bd,1H),7.18(d,2H),6.99(t,1H),6.06-6-05(m,2H),5.41(s,1H),4.62(s,1H),4.17-4.02(m,6H),3.80(s,1H),3.17(t,2H),2.57(bs,1H),2.43(bs,1H),2.31-2.23(m,1H),1.85(s,3H),1.78-1.73(m,1H),1.08(s,3H),1.04(s,3H),0.99(d,3H),0.95-0.90(m,1H),0.73-0.65(m,1H)。
embodiment 728:
ingenol 3-(azepan-1-manthanoate) (compound 728)
Compound 728 is prepared according to method e.
Raw material: compound 828.
1HNMR(300MHz,CDCl 3)δ6.04-6.02(m,1H),5.98(m,1H),5.20-5.19(m,1H),5.87-5.85(m,1H),4.13-4.08(m,3H),4.03-4.01(m,1H),3.84-3.81(m,1H),3.47-3.26(m,4H),2.80-2.76(m,1H),2.55-2.50(m,1H),2.30-2.22(m,1H),1.80(d,3H),1.75-1.56(m,9H),1.11(s,3H),1.04(s,3H),0.94(d,3H),0.91-0.86(m,1H),0.72-0.65(m,1H)。
embodiment 729:
ingenol 3-(N-(the chloro-phenyl of 4-)-N-Methyl-carbamic acid ester) (compound 729)
Compound 729 is prepared according to method e.
Raw material: compound 829.
1HNMR(300MHz,CDCl 3)δ7.35-7.30(m,2H),7.23-7.20(m,2H),6.00(d,1H),5.93(bs,1H),5.34(s,1H),4.48(bs,1H),4.13-4.05(m,3H),3.98(s,1H),3.60(s,1H),3.30(s,3H),2.62(bs,1H),2.15-2.10(m,1H),1.75(s,3H),1.70-1.64(m,2H),1.09(s,3H),1.05(s,3H),0.94-0.86(m,4H),0.70-0.62(m,1H).
embodiment 730:
ingenol 3-(N-(the fluoro-phenyl of 4-)-N-Methyl-carbamic acid ester) (compound 730)
Compound 730 is prepared according to method e.
Raw material: compound 830.
1HNMR(300MHz,CDCl 3)δ7.28-7.01(m,4H),6.00-5.98(m,1H),5.91(bs,1H),5.34(s,1H),4.48(bs,1H),4.11-4.04(m,3H),3.97(d,1H),3.59(bs,1H),3.29(s,3H),2.71(bs,1H),2.12(bs,1H),1.74(s,3H),1.60(bs,2H),1.09(s,3H),1.05(s,3H),0.94-0.87(m,1H),0.73(bs,3H),0.69-061(m,1H)。
embodiment 731:
ingenol 3-(N-methyl-N-(2-methoxyl group-phenyl)-carbamate) (compound 731)
Compound 731 is prepared according to method e.
Raw material: compound 831.
1HNMR(300MHz,CDCl 3)δ7.32-7.28(m,1H),7.19(d,1H),7.02-6.98(m,2H),5.99(d,1H),5.82(d,1H),5.68(bs,1H),4.24(s,1H),4.12(s,2H),3.98(d,1H),3.88-3.80(m,4H),3.30-3.24(m,4H),2.40(bs,1H),1.95-1.91(m,1H),1.72(d,3H),1.55-1.48(m,2H),1.10(s,3H),1.04(s,3H),0.95-0.87(m,1H),0.64-0.55(m,4H)。
embodiment 732:
ingenol 3-(N-methyl-N-(2-methylphenyl)-carbamate) (compound 732)
Compound 732 is prepared according to method e.
Raw material: compound 832.
1HNMR(300MHz,CDCl 3)δ7.23-7.16(m,4H),6.04-5.80(m,2H),5.41(s,1H),4.11-3.90(m,4H),3.24-3.16(m,4H),2.29-2.19(m,4H),1.77(s,3H),1.72-1.45(m,4H),1.06-1.02(m,6H),0.92-0.83(m,1H),0.64-0.56(m,4H)。
embodiment 733:
ingenol 3-(3-oxo-2,4-dihydro-quinoxaline-1-manthanoate) (compound 733)
Compound 733 is prepared according to method e.
Raw material: compound 833.
1HNMR(300MHz,CDCl 3)δ8.72(bs,1H),7.68(bd,1H),7.16-7.10(m,1H),7.06-7.03(m,1H),6.90(dd,1H),6.04-6.02(m,2H),5.57(s,1H),4.72(d,1H),4.49(d,1H),4.39(d,1H),4.20-4.11(m,3H),4.02-4.00(m,2H),2.77(bs,1H),2.31-2.17(m,2H),1.82(d,3H),1.68-1.60(m,1H),1.06(s,3H),1.04(s,3H),0.93-0.84(m,4H),0.70-0.62(m,1H)。
embodiment 734:
ingenol 3-(N-ethyl, N-phenyl-carbamate) (compound 734)
Compound 734 is prepared according to method e.
Raw material: compound 834.
1HNMR(300MHz,CDCl 3)δ7.40-7.20(m,5H),5.99-5.97(d,1H),5.88(bs,1H),5.34(s,1H),4.09-3.93(m,5H),3.76-3.66(dq,2H),3.44(bs,1H),2.64(bs,1H),2.01(bs,1H),1.80-1.53(m,5H),1.18(t,3H),1.08(s,3H),1.04(s,3H),0.95-0.89(m,1H),0.72-0.58(m,4H)。
embodiment 735:
ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) (compound 735)
Compound 735 is prepared according to method e.
Raw material: compound 835.
1HNMR(300MHz,CDCl 3)δ6.04-6.00(m,2H),5.31(s,1H),4.84(bs,1H),4.49-4.40(bd,1H),4.16-4.02(m,4H),3.83-3.47(m,3H),2.90(bs,1H),2.49(bs,1H),2.31-2.22(m,1H),2.13-1.91(m,4H),1.80-1.70(m,4H),1.10-1.09(2xs,3H),1.05(s,3H),0.97-0.89(m,4H),0.73-0.65(m,1H)。
embodiment 736:
ingenol 3-(3-azabicyclic [3.2.2] nonane-3-manthanoate) (compound 736)
Compound 736 is prepared according to method e.
Raw material: compound 836.
1HNMR(300MHz,CDCl 3)δ6.04-6.03(m,1H),5.99-5.98(m,1H),5.18(s,1H),4.77(bs,1H),4.12-4.07(m,3H),4.03(s,1H),3.84(s,1H),3.74-3.65(m,2H),3.59-3.50(m,2H),2.60(bs,1H),2.55-2.50(m,1H),2.29-2.21(m,1H),2.06-2.01(bd,2H),1.80(d,3H),1.78-1.62(m,9H),1.11(s,3H),1.04(s,3H),0.99-0.90(m,4H),0.72-0.65(m,1H)。
embodiment 737:
ingenol 3-(2,3-dihydro-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate) (compound 737)
Compound 737 is prepared according to method e.
Raw material: compound 837.
1HNMR(300MHz,CDCl 3)δ7.81(bs,1H),7.05-6.99(m,1H),6.91-6.84(m,2H),6.06-6.05(m,1H),5.98-5.96(m,1H),5.49(s,1H),4.77(s,1H),4.29(t,2H),4.17-4.11(m,3H),4.05-3.86(m,3H),3.75(s,1H),2.71(s,1H),2.45-2.40(m,1H),2.29-2.20(m,1H),1.83(d,3H),1.73-1.64(m,1H),1.06(s,3H),1.05(s,3H),0.94-0.86(m,4H),0.71-0.63(m,1H)。
embodiment 738:
ingenol 3-(N-(the fluoro-phenyl of 2-)-N-Methyl-carbamic acid ester) (compound 738)
Compound 738 is prepared according to method e.
Raw material: compound 838.
1HNMR(300MHz,CDCl 3)δ7.31-7.24(m,2H),7.17-7.08(m,2H),6.00-5.98(m,1H),5.85(s,1H),5.44(s,1H),4.18-3.92(m,6H),3.53(s,1H),3.28(s,3H),2.68(s,1H),2.08-2.00(m,1H),1.80(d,3H),1.8-1.7(m,1H),1.08(s,3H),1.04(s,3H),0.93-0.89(m,1H),0.68-0.60(m,4H)。
embodiment 739:
ingenol 3-(3-methyl-2,3-dihydros-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate) (compound 739)
Compound 739 is prepared according to method e.
Raw material: compound 839.
1HNMR(300MHz,CDCl 3)δ7.98-7.95(d,1H),7.05-6.98(m,1H),6.91-6.85(m,2H),6.08-5.96(m,2H),5.48(s,1H),4.88(s,1H),4.73-4.68(m,1H),4.20-4.04(m,6H),3.83(s,1H),2.75(s,1H),2.54-2.48(m,1H),2.38-2.29(m,1H),1.81(d,3H),1.79-1.72(m,1H),1.25(d,3H),1.09(s,3H),1.06(s,3H),0.97(d,3H),0.91-0.86(m,1H),0.74-0.64(m,1H)。
embodiment 740:
ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) (isomer A) (compound 740)
Compound 740 is prepared according to method e.Compound 740 is the first isomer collected from chromatogram purification.
Raw material: compound 835.
1HNMR(300MHz,CDCl 3)δ6.06-6.02(m,2H),5.26(s,1H),4.51(s,1H),4.39(s,1H),4.14-3.97(m,4H),3.86-3.51(m,3H),2.50-2.02(m,7H),1.81(s,3H),1.80-1.71(m,1H),1.10(s,3H),1.05(s,3H),0.96(d,3H),0.95-0.90(m,1H),0.73-0.66(m,1H)。
embodiment 741:
ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) (isomer B) (compound 741)
Compound 741 is prepared according to method e.Compound 741 is the second isomer collected from chromatogram purification.
Raw material: compound 835.
1HNMR(300MHz,CDCl 3)δ6.06-6.00(m,2H),5.25(s,1H),4.59-4.43(m,2H),4.14-4.03(m,4H),3.72-3.52(m,3H),2.50-2.02(m,7H),1.81-1.72(m,4H),1.11(s,3H),1.05(s,3H),0.99-0.93(m,4H),0.71-0.66(m,1H)。
embodiment 742:
ingenol 3-(N-methyl-N-(N-(t-butyloxycarbonyl)-4-piperidyl)-carbamate) (compound 742)
Compound 742 is prepared according to method e.
Raw material: compound 842.
1HNMR(300MHz,CDCl 3)δ6.05-6.03(m,1H),6.00(bs,1H),5.26-5.22(m,1H),4.75-4.68(m,1H),4.20-4.02(m,7H),3.74(s,1H),2.80-2.51(m,7H),2.29-2.20(m,1H),1.80(d,3H),1.78-1.62(m,5H),1.47(s,9H),1.10(s,3H),1.05(s,3H),0.99-0.93(m,4H),0.73-0.65(m,1H)。
embodiment 743:
ingenol 3-(N-methyl-N-(3-methylphenyl)-carbamate) (compound 743)
Compound 743 is prepared according to method e.
Raw material: compound 843.
1HNMR(300MHz,CDCl 3)δ7.27-7.22(m,1H),7.09-7.04(m,3H),5.98-5.97(m,1H),5.91(bs,1H),5.33(s,1H),4.11-3.94(m,5H),3.48(bs,1H),3.30(s,3H),2.54(bs,1H),2.35(s,3H),2.03(bs,1H),1.77(s,3H),1.65-1.56(m,2H),1.08(s,3H),1.04(s,3H),0.93-0.75(m,4H),0.67-0.59(m,1H)。
embodiment 744:
ingenol 3-(3,4-dihydro-2H-quinoxaline-1-manthanoate) (compound 744)
Compound 744 is prepared according to method e.
Raw material: compound 844.
1HNMR(300MHz,CDCl 3)δ7.87(bd,1H),7.67(bd,1H),7.23-7.11(m,2H),6.07-6.05(m,2H),5.50(s,1H),4.64(d,1H),4.19-3.96(m,9H),3.78(s,1H),2.39-2.22(m,3H),1.84(d,3H),1.75-1.67(m,1H),1.09(s,3H),1.05(s,3H),0.96-0.85(m,4H),0.72-0.64(m,1H)。
embodiment 745:
ingenol 3-(isoindoline-2-manthanoate) (compound 745)
Compound 745 is prepared according to method e.
Raw material: compound 845.
1HNMR(300MHz,CDCl 3)δ7.31-7.25(m,4H),6.05-6.03(m,2H),5.36(s,1H),4.89(bs,1H),4.75(s,4H),4.17-4.04(m,5H),3.94(s,1H),2.61-2.56(m,1H),2.33-2.24(m,1H),1.83(d,3H),1.81-1.71(m,1H),1.08(s,3H),1.02(s,3H),1.00(d,3H),0.98-0.90(m,1H),0.73-0.65(m,1H)。
embodiment 746:
ingenol 3-(N-methyl-N-(tetrahydropyran-4-base methyl)-carbamate) (compound 746)
Compound 746 is prepared according to method e.
Raw material: compound 846.
1HNMR(300MHz,CDCl 3)δ6.05-6.01(m,2H),5.20(d,1H),4.74(s,1H),4.11-3.95(m,6H),3.78(d,1H),3.41-3.31(m,2H),3.23-3.11(m,2H),2.96(s,3H),2.67(bs,1H),2.53-2.51(m,1H),2.29-2.19(m,1H),1.94-1.86(m,1H),1.80-1.70(m,4H),1.59-1.54(m,2H),1.40-1.27(m,2H),1.09(s,3H),1.05(s,3H),0.98-0.88(m,4H),0.73-0.65(m,1H)。
embodiment 747:
ingenol 3-(N-methyl-N-(tetrahydropyran-4-base)-carbamate) (compound 747)
Compound 747 is prepared according to method e.
Raw material: compound 847.
1HNMR(300MHz,CDCl 3)δ6.05-6.03(m,1H),6.00(bs,1H),5.23(bs,1H),4.73(bs,1H),4.25(bs,1H),4.13-4.01(m,6H),3.75(s,1H),3.50-3.39(m,2H),2.83(s,3H),2.68(bs,1H),2.52(bs,1H),2.29-2.20(m,1H),1.82-1.65(m,8H),1.10(s,3H),1.05(s,3H),0.99-0.92(m,4H),0.73-0.65(m,1H)。
embodiment 748:
ingenol 3-(N-methyl-N-(3-methoxyl group-phenyl)-carbamate) (compound 748)
Compound 748 is prepared according to method e.
Raw material: compound 848.
1HNMR(300MHz,CDCl 3)δ7.29-7.24(m,1H),6.86-6.80(m,3H),5.98-5.96(m,1H),5.92(bs,1H),5.36(s,1H),4.16-3.93(m,5H),3.80(s,3H),3.52(bs,1H),3.31(s,3H),2.63(bs,1H),2.05(bs,2H),1.80-1.57(m,4H),1.08(s,3H),1.04(s,3H),0.95-0.89(m,1H),0.75(bs,3H),0.67-0.59(m,1H)。
embodiment 749:
ingenol 3-(N-cyclobutyl-N-Methyl-carbamic acid ester) (compound 749)
Compound 749 is prepared according to method e.
Raw material: compound 849.
1HNMR(300MHz,CDCl 3)δ6.04-6.03(d,1H),5.99-5.98(m,1H),5.18(s,1H),4.81-4.73(m,1H),4.60-4.35(bs,1H),4.12-4.00(m,4H),3.79(s,1H),2.89(s,3H),2.68(bs,1H),2.55-2.50(m,1H),2.30-2.22(m,1H),2.19-2.09(m,4H),1.79(d,3H),1.78-1.62(m,3H),1.10(s,3H),1.04(s,3H),0.99-0.92(m,4H),0.72-0.65(m,1H)。
embodiment 750:
ingenol 3-(N-allyl group-N-Methyl-carbamic acid ester) (compound 750)
Compound 750 is prepared according to method e.
Raw material: compound 850.
1HNMR(300MHz,CDCl 3)δ6.05-6.03(m,1H),6.00-5.98(m,1H),5.83-5.73(m,1H),5.25-5.14(m,3H),4.46(bs,1H),4.12-3.76(m,7H),2.94(s,3H),2.56-2.50(m,2H),2.28-2.21(m,1H),1.80(d,3H),1.78-1.70(m,1H),1.10(s,3H),1.05(s,3H),0.97-0.88(m,4H),0.73-0.65(m,1H)。
embodiment 751:
ingenol 3-(N-methyl-N-Propargyl-carbamate) (compound 751)
Compound 751 is prepared according to method e.
Raw material: compound 851.
1HNMR(300MHz,CDCl 3)δ6.05-6.02(m,2H),5.38(bs,1H),4.21-4.01(m,7H),3.80(bs,1H),3.02(s,3H),2.51(bs,2H),2.30-2.21(m,2H),1.81(d,3H),1.78-1.71(m,1H),1.10(s,3H),1.05(s,3H),0.99-0.90(m,4H),0.73-0.65(m,1H)。
embodiment 752:
ingenol 3-(N-methyl-N-(4-methylthiazol-2-base)-carbamate) (compound 752)
Compound 752 is prepared according to method e.
Raw material: compound 852.
1HNMR(300MHz,CDCl 3)δ6.53-6.52(m,1H),6.11-6.10(m,1H),6.07-6.05(m,1H),5.52(s,1H),4.41(bs,1H),4.19-4.05(m,5H),3.61(s,3H),2.56-2.51(m,1H),2.35(d,3H),2.34-2.25(m,2H),1.85(d,3H),1.83-1.71(m,1H),1.08(s,3H),1.05(s,3H),0.98(d,3H),0.96-0.90(m,1H),0.74-0.66(m,1H)。
embodiment 753:
ingenol 3-(N-(4-cvano-phenyl)-N-Methyl-carbamic acid ester) (compound 753)
Compound 753 is prepared according to method e.
Raw material: compound 853.
1HNMR(300MHz,CDCl 3)δ7.66-7.62(m,2H),7.49-7.44(m,2H),6.02-6.00(m,1H),5.99-5.97(m,1H),5.41(s,1H),4.76(d,1H),4.15-4.09(m,3H),4.03-4.01(m,1H),3.75(s,1H),3.37(s,3H),2.73(t,1H),2.28-2.19(m,2H),1.77(d,3H),1.71-1.62(m,1H),1.09(s,3H),1.06(s,3H),0.95-0.82(m,4H),0.72-0.64(m,1H)。
embodiment 1
neutrophil leucocyte oxidative burst:
By the erythrocytic dissolving of continuous sedimentation, density centrifugation and pollution from fresh buffy coat abstraction and purification PMN ' s (polymorphonuclear leukocyte).Buffy coat 2% methylcellulose gum is incubated 30-45 minute with relative settlement erythrocyte.Leukocytic supernatant liquor will be rich in transfer in separation of lymphocytes pipe to remove monocyte by density centrifugation (400 × g, 30min).Any remaining red corpuscle 0.2%NaCl being dissolved 30 seconds by cell mass Eddy diffusion, then recovering isotonic by adding 1.2%NaCl.Repeat this step to cell mass to look substantially not containing red blood cell.Face start test before, by cell Eddy diffusion in DPBS (Dulbecco's phosphate buffered saline (PBS)) (w.o.Ca 2+, Mg 2+) and at HBSS (Hanks the balanced salt solution) (wCa containing 0.1%BSA (bovine serum albumin) and 5mM glucose 2+, Mg 2+) in by concentration adjustment to 1.4 × 10 6cell/ml.Titration reference substance and testing compound and HE (Hydroethidine) are pre-mixed (the final experimental concentration of 10 μMs), then join containing 2.5 × 10 5in the 96-orifice plate of individual cell.After at room temperature hatching 40 minutes, Envision plate reader is utilized to estimate the change in respiratory burst by the fluorescence being determined at 579nm (exciting: 485nm) place.
The effect standard of testing compound is changed into positive control (5 × 10 -7mPEP0005) after effect, by testing compound titration curve matching to four parameter sigmoidal curve.RelEC 50represent the test compounds substrate concentration of the effect of top and the centre, bottom producing and be positioned at matching.AbsEC 50cause to be equivalent to positive control (5 × 10 -7mPEP0005) maximum efficiency 50% the test compounds substrate concentration of response.
Embodiment 2
heKa release of cytokines (IL-8):
In the day before yesterday of test, primary human epidermic keratinocyte HeKa is inoculated (10.000 cells/well) in 96-orifice plate.Testing compound dilution in DMSO (dimethyl sulfoxide (DMSO)) is also diluted further in test(ing) medium, is then moved in the hole containing 96 orifice plates of HeKa cell.Plate is being contained 5%CO at 37 DEG C 2humidifying air in insulation 6 hours.By centrifugal with sedimentation cell for plate short period of time at 4 DEG C, removing supernatant liquor also passes through MesoScaleDiscovery (MSD) 4-point CYTOKINE ASSAYS (Pro-inflammatoryIIUltraSensitive test kit, MSD, MD, USA) analyze.MSD test adopts sandwich immunoassay form, wherein capture antibody is changed in mode the bottom that array is coated in the hole of 4-Spot-Multi-MSD plate.Also be incubated in MULTI-SPOT plate by standard model, cytokine (IL-8) is attached in its corresponding capture antibody dots.Cytokine levels is at SECTOR tMimager is upper utilizes the cytokine through MSDSULFO-TAGTM reagent mark to detect antibody quantitatively.
The effect standard of testing compound is changed into positive control (1.5 × 10 -7mPEP0005) after effect, by testing compound titration curve matching to four parameter sigmoidal curve.RelEC 50represent the test compounds substrate concentration of the effect of top and the centre, bottom producing and be positioned at matching.AbsEC 50cause to be equivalent to positive control (1.5 × 10 -7mPEP0005) maximum efficiency 50% the test compounds substrate concentration of response.
embodiment 3
downright bad experiment
HeLa cell (ATCCCCL-002) is grown in containing the minimum essential medium (Invitrogen catalog number 42360) of 10% foetal calf serum, 100IU/ml penicillin and 100 μ g/ml Streptomycin sulphates.By 4,000-6,000 cell inoculates the 100 μ l substratum also incubated overnight in 96-hole black ViewPlates plate (PerkinElmer) being arranged in clear bottom.Dissolved and beforehand dilution with DMSO in 96-hole polypropylene board (Greiner) by compound, concentration range is 15 μMs to 600 μMs.When testing, be placed in by cell plate on the heat block of 37 DEG C, removing substratum also adds the fresh pre-heated substratum of 40 μ l in every hole.By cell incubation 15 minutes, then add compound.Meanwhile, 3 μ l compounds, 197 μ l growth mediums are diluted with the liquid speed of moving of 250 μ l/s, to ensure that the compound solution of high density mixes with the effective of aqueous phase on TecanFreedom-EVO liquor removing workstation.Then the plate of these beforehand dilutions is balanced 10 minutes at 37 DEG C on heat block.Transfer to corresponding containing in the hole of HeLa cell by manual for the compound of 80 μ l beforehand dilutions, obtaining compound concentration is 10 μMs to 400 μMs.Collating condition contains 400 μMs of ingenol methyl butene acid esters (0% survival) containing in 1%DMSO (100% survival) and growth medium in growth medium.Plate is incubated 30 minutes on heat block at 37 DEG C.At the end of insulation, add 10 μ lPrestoBlue reagent (Invitrogen) in each hole, by plate black sealer sealing, then at 37 DEG C, under gentleness vibration, (150rpm) is incubated 10 minutes.Subsequently, plate is at room temperature placed 20-30 minute.Subsequently by plate reading on EnvisionFluorescence reader (PerkinElmer) immediately, excite at 535nm and launch at 630nm.The effect standard of testing compound is changed into positive control (410 -4mPEP0005/ ingenol methyl butene acid esters) effect after, by testing compound titration curve matching to four parameter sigmoidal curve.AbsEC 50represent the concentration of the testing compound of generation 50% effect.
The compounds of this invention is tested according to being described in the test of neutrophil leucocyte oxidative burst of embodiment 1, tests according to being described in HeKa cytokine release assay of embodiment 2, test according to being described in necrosis experiment of embodiment 3.
The RelEC of the compounds of this invention in the test of neutrophil leucocyte oxidative burst 50value is less than 10000nM, the RelEC in HeKa cytokine release assay 50value is less than 10000nM.
The RelEC of neutrophil leucocyte oxidative burst 50scope
* RelEC is shown 50value>=100nM
* shows RelEC 50value>=20nM and <100nM
* * shows RelEC 50value <20nM
HeKa release of cytokines (IL-8) RelEC 50scope
* RelEC is shown 50value>=100nM
* shows RelEC 50value>=20nM and <100nM
* * shows RelEC 50value <20nM
The EC of HeLa necrosis 50scope
* EC is shown 50value>=350 μm
* shows EC 50value>=150 μm and <350 μm
* * shows EC 50value <150 μm
Result is as shown in the table
embodiment 4
for evaluating the B16-F0 murine melanoma model of antitumor effect
By B16-F0 mouse melanin tumor cell ( numbering CRL-6322 tM) in the RPMI-1640glutaMAX (Invitrogen, catalog number 61870-010) being supplemented with 10% foetal calf serum and 1% Pen .-Strep (Invitrogen, catalog number 15140-122) at 37 DEG C, containing 5%CO 2humidifying air in cultivate.At the 0th day of experiment, by with TrypLE (Invitrogen, catalog number 12605-010) tryptic digestion results B16-F0 cell (70-90% fusions), wash, Eddy diffusion is in RPMI-1640glutaMAX and preserve on ice.In 30 minutes, will containing 0.5x10 650 μ l volume intradermal injections of the B16-F0 cell of individual work are to the waist shaving light hair of female C57BL/6JbomTac mouse in 10 week age, and every injected in mice once.At the 4th day of experiment, tumour electronic caliper (Mahr16ExH100207) is measured, gross tumor volume following formula is estimated: gross tumor volume=1/2* (longest diameter) * (orthogonal diameters) ^2.By tumor size at 9 to 60mm 3mouse in scope comprises under study for action and assigns in treatment group according to the size of tumour.By tumour solution every day 1 time, the continuous 2 day Local treatment of 20 μ l containing 0.1% testing compound.Solvent is comprised as negative control in each experiment.Every day measures tumour, and when the estimation volume of tumour is more than 250mm 3time by rat euthanasia.Do not consider the size of tumour, tumour is festered or the rat euthanasia that goes to bits to be included in data analysis as check object equally.Within 90th day, terminate experiment in experiment, 250mm will be less than in this day tumour 3mouse be also included in data analysis as check object.Draw KaplanMeier survivorship curve by tumour >250mm 3be appointed as death incident, carried out the comparison of survivorship curve by Log-rank inspection.Specifically, by the tumor growth of each treatment group compared with the tumor growth of solvent group, to evaluate the effect that often kind of compound is cured tumour or postponed tumor growth.P-value is considered to effective lower than 0.05.
Some the compounds of this invention are tested in B16-F0 murine melanoma model.Compound Be very effective being better than solvent is listed in the following table.

Claims (23)

1. compound of Formula I and pharmacologically acceptable salt thereof
Wherein R is heteroaryl, and described heteroaryl is different azoles base, pyridyl, quinolyl, isoquinolyl, indyl, furyl, thiazolyl, imidazolyl, pyrazolyl, azoles base, thienyl, pyrimidyl, 1,2,3-triazoles base, indazolyl, cinnolines base, 1,2-benzo azoles base, Imidazothiazole base, imidazopyridyl, pyrryl, isothiazolyl, tetrahydrochysene indazole base or di azoly, wherein said heteroaryl optionally replace by one or more substituting group independently selected from R7;
Or R is Heterocyclylalkyl or heterocycloalkenyl, wherein said Heterocyclylalkyl or heterocycloalkenyl are pyrrolidyl, piperidyl, morpholinyl, 5-oxabicyclo [2.2.2] octyl, oxaspiro [4.5]-1-in last of the ten Heavenly stems thiazolinyl, oxo-thiazol base, dihydro-thiazolyl, oxo-pyranyl, azepan base, azabicyclic [3.2.2] nonyl, benzo piperazine base, quinoxalinyl, dihydro-iso indolyl, dihydroquinoline base, indolinyl or dihydro-quinoxaline base, wherein said Heterocyclylalkyl or heterocycloalkenyl optionally replace by one or more substituting group independently selected from R8;
R7 represents halogen, cyano group or hydroxyl;
Or R7 represents (C 1-C 4) alkyl, (C 2-C 4)-alkenyl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, aryl, aryl-(C 1-C 4) alkyl, Heterocyclylalkyl-(C 1-C 4) alkyl or (C 3-C 7)-cycloalkyl-(C 1-C 4) alkyl, wherein said Heterocyclylalkyl represents piperidyl or THP trtrahydropyranyl and Aryl stands phenyl, wherein said (C 1-C 4) alkyl, (C 2-C 4)-alkenyl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, aryl, aryl-(C 1-C 4) alkyl, Heterocyclylalkyl-(C 1-C 4) alkyl or (C 3-C 7)-cycloalkyl-(C 1-C 4) alkyl optionally replace by one or more substituting group independently selected from R9;
Or R7 representative-ORa;
R9 represents halogen, cyano group, hydroxyl, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl ,-SO 2ra or-ORa; R8 represents halogen, cyano group or hydroxyl;
Or R8 represents (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl or (C 3-C 7)-cycloalkyl, Aryl stands phenyl wherein, wherein said (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl or (C 3-C 7)-cycloalkyl optionally replace by one or more substituting group independently selected from R10;
Or R8 represents-COORc or=O;
R10 represents halogen, cyano group, hydroxyl, (C 1-C 4)-alkyl, (C 1-C 4) alkoxyl group, halo (C 1-C 4) alkyl, halo (C 1-C 4) alkoxyl group, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl or (C 3-C 8)-cycloalkyl;
Ra and Rb represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl or (C 3-C 8)-cycloalkyl;
Rc represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl, cyano group (C 1-C 4) alkyl or (C 3-C 8)-cycloalkyl.
2. compound according to claim 1,
Wherein R is heteroaryl, its optionally replace by one or more substituting group independently selected from R7,
Or R is Heterocyclylalkyl or heterocycloalkenyl, each in them is all optionally replaced by one or more substituting group independently selected from R8;
R7 represents halogen, cyano group, hydroxyl;
Or R7 represents (C 1-C 4) alkyl, (C 2-C 4)-alkenyl, (C 3-C 7)-cycloalkyl, Heterocyclylalkyl, aryl, each in them is all optionally replaced by one or more substituting group independently selected from R9;
Or R7 representative-ORa;
R9 represents halogen, cyano group, hydroxyl, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl ,-SO 2ra or-ORa; R8 represents halogen, cyano group, hydroxyl;
Or R8 represents (C 1-C 4)-alkyl, (C 2-C 4) alkenyl, aryl or (C 3-C 7)-cycloalkyl, each in them is all optionally replaced by one or more substituting group independently selected from R10,
Or R8 represents-COORc or=O;
R10 represents halogen, cyano group, hydroxyl, (C 1-C 4)-alkyl or halo (C 1-C 4) alkyl;
Ra and Rb represents hydrogen, (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl or cyano group (C 1-C 4) alkyl;
Rc represents (C 1-C 4) alkyl, halo (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group (C 1-C 4) alkyl, hydroxyl (C 1-C 4) alkyl or cyano group (C 1-C 4) alkyl.
3. the compound described in claim 1 or 2, wherein R is heteroaryl.
4. the compound described in claim 1 or 2, wherein R7 is independently selected from (C 1-C 4) alkyl, (C 2-C 4) alkenyl, aryl, aryl-(C 1-C 4) alkyl, Heterocyclylalkyl-(C 1-C 4) alkyl, (C 3-C 7)-cycloalkyl-(C 1-C 4) alkyl, (C 3-C 7)-cycloalkyl ,-ORa or halogen.
5. compound according to claim 1, wherein R7 is selected from phenyl, methyl, ethyl, sec.-propyl, the tertiary butyl, piperidyl, benzyl, tetrahydropyrans ylmethyl ,-OCH 3, cyclopropyl, allyl group, Cvclopropvlmethvl, Cl, Br or I.
6. the compound described in claim 1 or 2, wherein R9 is halogen ,-ORa, (C 1-C 4) alkyl or-SO 2ra.
7. compound according to claim 6, wherein R9 is Cl, F ,-OCH 3, methyl or methyl sulphonyl.
8. compound according to claim 1, wherein R is Heterocyclylalkyl or heterocycloalkenyl.
9. the compound described in claim 1 or 8, wherein R8 is (C 1-C 4) alkyl, aryl or=O.
10. compound according to claim 9, wherein R8 is methyl, phenyl or=O.
Compound described in 11. claims 1 or 2, wherein R10 represents halogen.
12. compounds according to claim 1, described compound is selected from:
Ingenol 3-(5-methyl-3-phenyl-different azoles-4-manthanoate),
Ingenol 3-(5-methyl-3-(the fluoro-phenyl of the chloro-6-of 2-)-different azoles-4-manthanoate),
Ingenol 3-(1S-camphane acid esters),
Ingenol 3-(3-Phenyltriazole-4-manthanoate),
Ingenol 3-(2-phenylpyrazole-3-manthanoate),
Ingenol 3-(1-methyl-benzdiazole-3-formic acid ester),
Ingenol 3-(3-ethyl-5-methyl-different azoles-4-manthanoate),
Ingenol 3-(3-methyl-5-methyl-different azoles-4-manthanoate),
Ingenol 3-(1-skatole-3-manthanoate),
Ingenol 3-(3-tolylthiophene-2-manthanoate),
(5-phenyl is different for ingenol 3- azoles-3-manthanoate),
Ingenol 3-(morpholine-4-manthanoate),
Ingenol 3-(tetramethyleneimine-1-manthanoate),
Ingenol 3-(piperidines-1-manthanoate),
Ingenol 3-(3,3-DimethYI-pineridin-1-manthanoate),
Ingenol 3-(isoquinoline 99.9-1-manthanoate),
Ingenol 3-(quinoline-4-manthanoate),
Ingenol 3-(cinnolines-4-manthanoate),
Ingenol 3-(3-phenylimidazole-4-manthanoate),
Ingenol 3-(5-phenyl azoles-4-manthanoate),
Ingenol 3-(1,2-benzo azoles-3-manthanoate),
Ingenol 3-(3-sec.-propyl-5-methyl-different azoles-4-manthanoate),
Ingenol 3-(3-(2-p-methoxy-phenyl)-5-methyl-different azoles-4-manthanoate),
Ingenol 3-(the bromo-2-methyl pyrazole of 4--3-manthanoate),
Ingenol 3-(4-bromo-2-ethyl-pyrazoles-3-manthanoate),
Ingenol 3-(4-chloro-2-methyl-pyrazoles-3-manthanoate),
Ingenol 3-(5-bromo pyrimi piperidine-4-manthanoate),
Ingenol 3-(3-bromopyridine-2-manthanoate),
Ingenol 3-(5-methylthiazol-4-manthanoate),
Ingenol 3-(the chloro-1-methyl pyrazole of 4--3-manthanoate),
Ingenol 3-(2,4-dimethylthiazole-5-manthanoate),
Ingenol 3-(2,5-dimethyl azoles-4-manthanoate),
Ingenol 3-(2,4-dimethyl furan-3-manthanoate),
(3,5-diethyl is different for ingenol 3- azoles-4-manthanoate),
Ingenol 3-(1H-indoles-7-manthanoate),
Ingenol 3-(the 2-tertiary butyl-5-methyl pyrazole-3-manthanoate),
Ingenol 3-(the 5-tertiary butyl-2-methyl pyrazole-3-manthanoate),
Ingenol 3-(6-Methylimidazole is [2,1-b] thiazole-5-manthanoate also),
Ingenol 3-(glyoxal ethyline is [1,2-a] Nicotinicum Acidum ester also),
Ingenol 3-(2,4,5-trimethylammonium furans-3-manthanoate),
Ingenol 3-(3 methyl thiophene-2-manthanoate),
Ingenol 3-(2-methyl-4-(piperidino) pyrazoles-3-manthanoate),
Ingenol 3-(the chloro-5-sec.-propyl-4-thiazolecarboxylic acid ester of 2-),
Ingenol 3-(chloro-2, the 5-Dimethyl-pyrazol-3-manthanoate of 4-),
Ingenol 3-(1,2,4-trimethylammonium pyrroles-3-manthanoate),
Ingenol 3-(1,3,5-trimethylammonium pyrroles-2-manthanoate),
Ingenol 3-(1-ethyl-3,5-dimethyl pyrrole-2-manthanoate),
Ingenol 3-(1-t-butyloxycarbonyl-3,3-dimethyl pyrrolidine-2-manthanoate),
Ingenol 3-((2S)-1-Phenylpyrrolidine-2-manthanoate),
Ingenol 3-(1-sec.-propyl-3,5-Dimethyl-pyrazol-4-manthanoate),
Ingenol 3-(5-ethyl-3-sec.-propyl-different azoles-4-manthanoate),
Ingenol 3-(2-methyl-benzdiazole-3-formic acid ester),
Ingenol 3-(5-methyl-3-the tertiary butyl-different azoles-4-manthanoate),
Ingenol 3-(2-methyl-3-oxo-4-oxaspiro [4.5]-1-in last of the ten Heavenly stems alkene-1-manthanoate),
Ingenol 3-(the 1-tertiary butyl-3,5-Dimethyl-pyrazol-4-manthanoate),
Ingenol 3-(3,5-dimethyl isothiazole-4-manthanoate),
Ingenol 3-(the iodo-3-methyl-isothiazol of 5--4-manthanoate),
Ingenol 3-(4-(4-p-methoxy-phenyl)-2-methyl pyrazole-3-manthanoate),
Ingenol 3-(4-(2-aminomethyl phenyl)-2-methyl pyrazole-3-manthanoate),
Ingenol 3-(2-methyl-4-(4-methylsulfonyl phenyl) pyrazoles-3-manthanoate),
Ingenol 3-(2-methyl 4-phenyl-pyrazoles-3-manthanoate),
Ingenol 3-(3,5-dimethyl-1-phenyl-pyrazole-4-manthanoate),
Ingenol 3-(1,5-dimethyl-3-phenyl-pyrazole-4-manthanoate),
Ingenol 3-(1-benzyl-3,5-Dimethyl-pyrazol-4-manthanoate),
Ingenol 3-(3,5-dimethyl-1-(tetrahydropyran-4-base methyl) pyrazoles-4-manthanoate),
Ingenol 3-(4-methyl-2-oxo-3H-thiazole-5-manthanoate),
Ingenol 3-(2-methyl-4,5,6,7-tetrahydrochysene indazole-3-manthanoate),
Ingenol 3-(1,2-dimethyl indole-3-manthanoate),
Ingenol 3-(5-methoxyl group-1,2-dimethyl-indol-3-manthanoate),
Ingenol 3-(1,3,5-trimethylpyrazol-4-manthanoate),
Ingenol 3-(4-methyl isophthalic acid, 2,5- diazole-3-manthanoate),
Ingenol 3-(2-methoxyl group-4-methyl-thiazole-5-manthanoate),
(4,5-dimethyl is different for ingenol 3- azoles-3-manthanoate),
Ingenol 3-(the bromo-1-methyl pyrazole of 4--3-manthanoate),
Ingenol 3-(1,3-dimethyl indole-2-manthanoate),
Ingenol 3-(5-methoxyl group-1,3-dimethyl-indol-2-manthanoate),
Ingenol 3-(2,4-dimethyl-6-oxo-pyrans-3-manthanoate),
Ingenol 3-(1-methyl-3-phenyl-indole-2-manthanoate),
(3-methyl-5-(trifluoromethyl) is different for ingenol 3- azoles-4-manthanoate),
Ingenol 3-(1,3-dimethyl pyrrole-2-manthanoate),
Ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl) pyrazoles-4-manthanoate),
Ingenol 3-(1-cyclopropyl-2,5-Dimethyl-pyrrol-3-manthanoate),
Ingenol 3-(1,2,5-trimethylammonium pyrroles-3-manthanoate),
Ingenol 3-(2,4-dimethyl-1H-pyrroles-3-manthanoate),
Ingenol 3-(1-methylpyrrole-2-manthanoate),
Ingenol 3-(4-methyl isophthalic acid H-pyrroles-2-manthanoate),
Ingenol 3-(1,5-dimethyl pyrrole-2-manthanoate),
Ingenol 3-(3-methyl isophthalic acid H-pyrroles-2-manthanoate),
Ingenol 3-(1-cyclopropyl pyrroles-2-manthanoate),
Ingenol 3-(1-ethyl-2,4-Dimethyl-pyrrol-3-manthanoate),
Ingenol 3-(1-allyl group-2,4-Dimethyl-pyrrol-3-manthanoate),
Ingenol 3-(1-(Cvclopropvlmethvl)-2,4-Dimethyl-pyrrol-3-manthanoate),
Ingenol 3-(1-(2-methoxy ethyl)-2,4-Dimethyl-pyrrol-3-manthanoate),
Ingenol 3-(4-oxo-2,3-dihydroquinoline-1-manthanoate),
Ingenol 3-(3,4-dihydro-2H-quinoline-1-manthanoate),
Ingenol 3-(indoline-1-manthanoate),
Ingenol 3-(azepan-1-manthanoate),
Ingenol 3-(3-oxo-2,4-dihydro-quinoxaline-1-manthanoate),
Ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate),
Ingenol 3-(3-azabicyclic [3.2.2] nonane-3-manthanoate),
Ingenol 3-(2,3-dihydro-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate),
Ingenol 3-(3-methyl-2,3-dihydros-Isosorbide-5-Nitrae-benzo piperazine-4-manthanoate),
Ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) isomer A,
Ingenol 3-(2-Trifluoromethyl-pyrrolidine-1-manthanoate) isomer B,
Ingenol 3-(3,4-dihydro-2H-quinoxaline-1-manthanoate),
Ingenol 3-(isoindoline-2-manthanoate).
Compound described in any one in 13. claim 1-12 is for the preparation of the purposes of medicine.
The purposes of 14. compounds according to claim 13, for the preparation for the treatment of, the medicine improving or prevent the physiological conditions relevant with hyperplasia or tumour or disease.
15. purposes according to claim 14, wherein said illness or disease are selected from tumor-like lesion or Vulvar intraepithelial neoplasia in cutaneous wart, Genital warts, actinic keratosis, squamous cell carcinoma (SCC), rodent cancer (BCC), malignant freckle, cervical intraepithelial neoplasia (CIN), anoderm.
The purposes of 16. compounds according to claim 13, for the preparation for the treatment of or the medicine improving beauty treatment indication.
17. purposes according to claim 16, beauty treatment indication is wherein selected from skin or the seborrheic keratosis of light injury.
The purposes of 18. compounds according to claim 13, has the pharmaceutical composition of the disease of response, illness or situation for the preparation for the treatment of or the stimulation that improves centering granulocyte oxidative burst.
The purposes of 19. compounds according to claim 13, for the preparation for the treatment of or improve the pharmaceutical composition that stimulation that Human Keratinocytes IL-8 discharges has the disease of response, illness or situation.
The purposes of 20. compounds according to claim 13, for the preparation for the treatment of or the pharmaceutical composition that improves the necrosis induced disease, illness or the situation that have a response.
21. pharmaceutical compositions, it comprises compound described in any one in claim 1-12 or its pharmaceutically useful steric isomer or salt and pharmaceutically acceptable carrier or vehicle.
22. pharmaceutical compositions according to claim 21, wherein said composition is suitable for topical.
23. pharmaceutical compositions, it comprises compound described in any one in the claim 1-12 combined with one or more other medical active agent or its pharmaceutically useful steric isomer or salt.
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